WO2014048165A1 - Compound as potassium channel modulator - Google Patents

Compound as potassium channel modulator Download PDF

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Publication number
WO2014048165A1
WO2014048165A1 PCT/CN2013/079617 CN2013079617W WO2014048165A1 WO 2014048165 A1 WO2014048165 A1 WO 2014048165A1 CN 2013079617 W CN2013079617 W CN 2013079617W WO 2014048165 A1 WO2014048165 A1 WO 2014048165A1
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Prior art keywords
compound
group
alkyl
preparation
cycloalkyl
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PCT/CN2013/079617
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French (fr)
Chinese (zh)
Inventor
陈焕明
梁波
赵忠强
曹文杰
徐万美
李清松
王江淮
张鹏
江兆建
张贵平
高春华
巩洪举
左高磊
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上海先声药物研究有限公司
江苏先声药物研究有限公司
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Publication of WO2014048165A1 publication Critical patent/WO2014048165A1/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a class of compounds which modulate potassium channels which are effective in the treatment and prevention of diseases and conditions which are affected by the activity of potassium ion channels.
  • KCNQ potassium channel is an important branch of the potassium channel superfamily. Five types of KCNQ1 5 have been found, and their gene mutations are associated with many hereditary diseases (Jentsch Natwre?eWe Nrara'ewce, 2000 1, 21-30). Among them, KCNQl (KvLQT) is mainly distributed in the myocardium, and 50% of hereditary LQT syndrome is associated with KCNQ1 mutation. KCNQ2-5 is mainly distributed in the central nervous system, inner ear (KCNQ4) and muscle tissue (KCNQ5). KCNQ2 and B KCNQ3 are the molecular basis of the M-type potassium channel of nerve cells, benign familial neonatal seizures (BFNC) and KCNQ2 KCNQ3. Down-regulation of M current caused by mutation of the gene. KCNQ4 is highly expressed in auditory-related nerve conduction pathways, nucleus and inner ear hair cells, and hereditary deafness (DFNA) is associated with KCNQ4 gene mutation.
  • DFNA
  • retigabine N-2-amino-4-(4-fluorobenzyl)-carbamic acid ethyl ester, which has a significant effect on partial seizures of intractable epilepsy. It was approved by the US FDA in June 2011. Listed as adjunctive medication for partial seizures in adult epilepsy. Retigabine has an open function on KCNQ potassium channel, which can effectively activate M-type potassium current and reduce neuron excitability. It has broad-spectrum and effective anticonvulsant effect, and is effective in hereditary epilepsy and different ignition models.
  • MES maximal electroconvulsive
  • PTZ pentylenetetrazol
  • NMDA N-methyl-D-aspartate
  • indomethacin kainate
  • penicillin potassium magnesium
  • pyrogenicity Stimulation-induced rodent seizures exhibit anticonvulsant activity (Luszczki JJ. Pharmacol Rep, 2009, 61, 197-216)
  • KCNQ potassium channel openers can be used to treat painful diseases.
  • the expression of KCNQ2 5 potassium channel RA in the trigeminal ganglion, dorsal root ganglia, and trigeminal caudate nucleus means that these channel openers may affect the sensory process of migraine (Goldstein et al, Society for Neuroscience Abstracts, 2003, 53).
  • retigabine also has potential therapeutic effects on anxiety, stroke, and neurodegenerative diseases.
  • KCNQ potassium channel opener has become a new direction for antiepileptic drug research.
  • due to the wide physiological function of KCNQ potassium channel its open agent also has a very broad application prospect.
  • Another object of the present invention is to provide a pharmaceutical use of the above compounds.
  • the object of the invention can be achieved by the following measures:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 10 aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro,
  • R 1 and R 2 in addition to the above given meanings, when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 together with the carbon atom to which they are bonded form a five or six member a saturated carbocyclic ring; when R 1 and R 2 are bonded to the same carbon atom, R 1 and R 2 together with the carbon atom to which they are bonded form a carbonyl group, a C 3 -C 6 cycloalkyl group or a benzo C 3 -C 6 cycloalkyl;
  • R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged cycloalkyl, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q aryl, heteroaryl, C 4 -C 8 heterocycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl or C 2 -C 6 block, and one or more selected from hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, c r c 6 alkyl, c 3 -c 6 cycloalkyl, c 6 -c 1Q aryl, c r c 6 ⁇ i alkyl, dc 6 alkoxy, Substituted by a substituent of dC 6 aminoalkyl or dC 6 ⁇ alkoxy; R 4 and R 5 are each independently hydrogen, halogen,
  • X and Y are each independently CH or N, wherein, when A is z4 v z3 , X and Y are CH;
  • Z 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
  • Z 2 and Z 5 are each independently CH or N;
  • Z 3 and Z 4 are each independently C, CH, CH 2 , N, NH or a covalent bond, wherein Z 2 and Z 3 do not simultaneously contain N;
  • Z 6 , Z 7 and Z 8 are each independently selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond, wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N , Z 6 , Z 7 and Z 8 are not covalent bonds at the same time;
  • p 1 or 2;
  • n is an integer from 0 to 6;
  • B is selected from C 3 -C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C 2 -C 1Q heteroaryl, C 4 -C 8 heterocycloalkyl or C 6 -C 10 bridge ring base; Among them, B ring and contains ⁇ everyone / everyone /
  • ⁇ is 1 or 2;
  • ⁇ is 0 or 1 ;
  • X and ⁇ are each independently CH or ⁇ ;
  • ⁇ 1 selected from a covalent bond or C r C 6 alkylene, wherein said C r C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or C r C 6 alkyl substituents;
  • R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl, C 4 a -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 block group, and one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Base, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl,
  • R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, dC 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, -C j alkenyl, C block basis 2 -C 6, C 6 -C 1Q aryl, C 3 -C 1Q -3 ⁇ 4 heteroaryl or heterocycloalkyl, wherein said C r C 6 alkyl, dC 6 alkoxy, C 3 - C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or 3 ⁇ 4
  • the heterocycloalkyl group is optionally independently selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, dC 6
  • Z 1 in formula II is CH 2 .
  • R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1 () aryl, and substituted with one or more substituents selected from hydrogen, halogen, cyano Substituted by a substituent of a nitro group, an amino group or a hydroxy group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane Base or phenyl.
  • R 4 and R 5 in the formula are each independently C r C 6 alkyl. More preferably, R 4 and R 5 are each independently methyl or ethyl.
  • R 6 and R 7 in the formula are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkenyl, C 2 a -C 6 block group, wherein the dC 6 alkyl group, the dC 6 alkoxy group, the C 2 -C 6 alkenyl group, the C 2 -C 6 block group are independently optionally one or more selected from the group consisting of hydrogen and halogen Substituted by a substituent of a cyano group, a nitro group, an amino group or a hydroxyl group. More preferably, R 6 and R 7 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
  • ( ⁇ ) z 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
  • Z 2 is CH or N
  • Z 3 and Z 4 are each independently C, CH, CH 2 , N, NH or a covalent bond, wherein Z 2 and Z 3 do not simultaneously contain N; n is 0 or 1;
  • R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged cycloalkyl, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q aryl, heteroaryl, a C 4 -C 8 heterocycloalkyl, c 3 -c 6 cycloalkenyl, c 2 -c 6 alkenyl or c 2 -c 6 block, and one or more selected from the group consisting of hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, c r c 6 alkyl, c 3 -c 6 cycloalkyl, c 6 -c 1Q aryl, c r c 6 ⁇ i alkyl, dc 6 alkoxy, Substituted by a substituent of dC 6 aminoalkyl or dC 6 ⁇ alkoxy;
  • R 4 and R 5 are each independently hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C r C 6 aminoalkyl, CC 6 alkylamino, dC 6 haloalkyl or dC 6 haloalkoxy;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, cyano, halogen, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, a c 2 -c 6 alkenyl group, a c 2 -c 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a c 4 -c 8 heterocycloalkyl group, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 10 aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from
  • R 8 and R 9 when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a c 3 -c 6 cycloalkyl group or a benzene group. And c 3 -c 6 cycloalkyl.
  • R 3 in formula III is selected from c r c 6 alkyl, c 3 -c 6 cycloalkyl or c 6 -c 1() aryl, and is selected from one or more selected from the group consisting of hydrogen, halogen, cyanide Substituted by a substituent of a nitro group, an amino group or a hydroxy group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane Base or phenyl.
  • R 4 and R 5 in formula III are each independently C r C 6 alkyl. More preferably, R 4 and R 5 are each independently methyl or ethyl.
  • R 8 and R 9 in the formula are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 a -C 6 cycloalkenyl group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group, wherein the dC 6 alkyl group, C r C 6 alkoxy group, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, optionally independently Or a plurality of substituents selected from the group consisting of hydrogen, halogen, dC 6 alkyl, dC 6 haloalkyl, dC
  • R 8 and R 9 are attached to the same carbon atom
  • R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a C 3 -C 6 cycloalkyl group or a benzo C 3 -C 6 cycloalkyl group.
  • R 8 and R 9 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl, 2-pyridyl, 3-pyridine group, 4-pyridyl, pyrrolidinyl, piperidinyl, N- morpholinyl, wherein said phenyl is optionally independently substituted with one or more substituents selected from hydrogen, halo, C r C 3 alkyl, C Substituting a substituent of r C 3 haloalkyl, C r C 3 alkoxy, C r C 3 haloalkoxy; or, in addition to the above given meaning, when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexane group or a
  • Z 1 in formula III is CH 2 .
  • Z 2 , Z 3 and Z 4 in the formula III contain N in at least one group; further preferably, the cyclic group containing Z 2 , Z 3 and Z 4 is piperidinyl, pyrrolidinyl Or piperazinyl.
  • X and Y are each independently CH or N;
  • Z 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
  • R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl, C 4 a -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 block group, and one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Base, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, dC 6 ⁇ alkyl, 6 alkoxy, C r C 6 aminoalkyl or Substituted by a substituent of C r C 6 ⁇ alkoxy;
  • R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
  • Z 5 is N or CH
  • Z 6 , Z 7 and Z 8 are each independently selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond, wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N, Z 6 , Z 7 and Z 8 are not simultaneously covalent bonds;
  • n is an integer from 1-6;
  • n 0 or 1;
  • B is selected from C 3 -C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C 2 -C 1Q heteroaryl, C 4 -C 8 heterocycloalkyl or C 6 -C bridge ring base; wherein, B ring and containing ⁇ ⁇ ,
  • R 1Q and R 11 are each independently selected from the group consisting of hydrogen, cyano, halogen, dC 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said dC 6 alkyl, dC 6 Alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -
  • the C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl group is optionally independently selected from one or more selected from the group consisting of hydrogen, halogen, cyano,
  • R 3 in formula IV is selected from the group consisting of C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 10 aryl, C 3 -C 1Qheteroaryl , c 4 -c 8 heterocycloalkyl, and one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carbonyl, C r C 3 alkyl, C r Substituted by a C 3 haloalkyl, C r C 3 alkoxy, C r C 3 aminoalkyl or C r C 3 haloalkoxy group.
  • R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane a phenyl group, an adamantyl group, a 2-furyl group, a pyrrolidinyl group, a pyrrolidinyl group or a cyclopropyl group, wherein a cyclopropyl group, a cyclohexyl group, a cyclopentyl group, a cyclobutyl group, a phenyl group, a 2-furyl group, a pyrrolidine group
  • the radicals are independently optionally substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, trifluo
  • Z 1 in formula IV is selected from a covalent bond or a dC 3 alkylene group, wherein the dC 3 alkylene group may be substituted with one or more substituents selected from hydrogen or c r c 3 alkyl.
  • R 4 and R 5 in formula IV are each independently hydrogen, halogen, cyano, dC 3 alkyl, dC 3 alkoxy, C r C 3 aminoalkyl, C r C 3 alkylamino or C r C 6 haloalkoxy; R 4 and R 5 are each independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy or trifluoromethoxy.
  • R 1Q and R 11 in formula IV are each independently selected from the group consisting of hydrogen, cyano, halogen, C r C 6 alkyl, C r C 6 alkoxy, wherein said dC 6 alkyl, dC 6 alkane
  • the oxy group is optionally substituted by one or more halogens.
  • R 1Q and R 11 are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or cyano.
  • the two adjacent linking bonds of the above preferred fluorene group are adjacent to the fluorene in the structure of the formula (IV), and actually constitute a structure in which the two rings are bonded.
  • ⁇ 5 in formula IV is ruthenium or CH; ⁇ 6 is selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond; Z 7 is selected from CH 2 , (CH) 2 ) 2 , NH or a covalent bond; wherein Z 6 and Z 7 are not simultaneously a covalent bond; Z 8 is selected from (CH 2 ) 2 , CH 2 or NH; ZN, C or CH; wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N.
  • the cyclic group (excluding ring B) containing Z 5 , ZZZ 8 and Z 9 in formula IV is piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, cyclohexyl , tetrahydropyrrolyl, hexahydroazepine or piperazinyl.
  • the structure of formula IV is the combination, X and Y are CH, Z 1 is, R 3 is tert-butyl, R 4 and R 5 are methyl, Z 5 is N, Z 6 , Z 7 and Z 8 are CH 2 , Z 9 is C, n is 0, B is R 1Q is H, and R 11 is fluorine, chlorine, bromine or methyl.
  • the structure of formula IV is the combination, X and Y are CH, Z 1 is methylene, R 3 is based, R 4 and R 5 are methyl, Z 5 is N, Z 6 is a covalent bond, Z 7 And Z 8 is (CH 2 ) 2 , Z 9 is C, n is 0, and B is
  • X and ⁇ are each independently CH or ⁇ ;
  • ⁇ 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
  • R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl, C 4 a -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 block group, and one or more selected from the group consisting of hydrogen, halogen, Cyano, nitro, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, dC 6 ⁇ alkyl, 6 alkoxy, C r C 6 a substituted aminoalkyl or C r C 6 ⁇ alkoxy group substituted by the group;
  • R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
  • D is a C 3 -C 1Q heteroaryl group, wherein D is not a pyrrolyl group and a benzimidazolyl group;
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said c r c 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 1Q aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano,
  • adjacent R 12 and R 13 together with a ring atom on the D group form a three to six membered saturated carbocyclic ring.
  • R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1Q aryl, and substituted with one or more substituents selected from hydrogen, halo, cyano, Substituted by a substituent of a nitro group, an amino group or a hydroxyl group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane Base or phenyl.
  • X and Y in formula V are each independently CH.
  • Z 1 in formula V is CH 2 ;
  • R 4 and R 5 in formula V are each independently dC 6 alkyl. More preferably, R 4 and R 5 are each independently methyl or ethyl.
  • R 12 and R 13 in formula V are each independently selected from the group consisting of hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 ring Alkenyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said Ci-C 6 moieties, Ci-Ce alkoxy, C 3 - a C 6 ring-based, C 3 -C 6 ring; Hirsch, C 6 -CKJ aryl, Cg-do heteroaryl or C 4 -Cs heterocycloalkyl optionally independently selected from one or more selected from hydrogen Substituted by halogen, cyano, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, dC 6 haloalkoxy; or adjacent R 12 and R
  • R 12 and R 13 are each independently hydrogen, cyano, fluoro, chloro, bromo, methyl or trifluoromethyl, or the adjacent R 12 and R 13 are bonded together with a ring atom on the D group.
  • a five- or six-membered saturated carbocyclic ring is formed, such as cyclopentane or cyclohexane.
  • D in formula V is selected from
  • alkyl denotes a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms.
  • c r c 6 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms.
  • dC 6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, dissident Base, 2,2-dimethylbutyl and 2,3-dimethylbutyl and the like.
  • dC 3 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms.
  • d- 6 alkylene denotes a saturated divalent hydrocarbon radical having from 1 to 6 carbon atoms which is derived by the removal of two hydrogen atoms from a linear or branched saturated hydrocarbon, including but not limited to methylene, ethylene Base, isopropylidene, etc.
  • alkoxy denotes 0-alkyl.
  • C r C 6 alkoxy refers to an alkyl group having 0- CC 6.
  • halogen is fluoro, chloro, bromo or iodo. Preferred are fluorine, chlorine, and bromine.
  • haloalkyl denotes an alkyl group having one or more (including one) halogen substituent.
  • haloalkoxy denotes an alkoxy group having one or more (including one) halogen substituent.
  • cycloalkyl denotes a saturated monocyclic or polycyclic ring structure which is all carbon atoms.
  • C 3 -C 6 cycloalkyl refers to a saturated monocyclic or polycyclic ring structure having a total of from 3 to 6 carbon atoms.
  • C 3 -C 6 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • cycloalkenyl refers to a monocyclic or polycyclic hydrocarbyl substituent having at least one cyclic carbon-carbon double bond.
  • C 3 -C 6 cycloalkenyl refers to a cycloalkenyl group of 3 to 6 carbon atoms.
  • C 3 -C 6 cycloalkenyl includes, but is not limited to, cyclopentenyl, cyclobutenyl.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms.
  • C 2 -C 6 block group means a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms.
  • C 6 -C 1Q aryl denotes an all-carbon monocyclic or fused polycyclic group of 6 to 10 carbon atoms having a fully conjugated ⁇ -electron system. Typically, but not limited to, phenylcyclo, naphthalene ring.
  • heteroaryl denotes a monocyclic or fused ring radical containing one, two, three or four ring heteroatoms selected from N, 0 or S, the remaining ring atoms being C and additionally fully conjugated. ⁇ electronic system.
  • C 2 -C 1Q heteroaryl means a heteroaryl group having 2 to 10 carbon atoms in its ring, and the heteroaryl group further includes one or more hetero atoms in the ring atom.
  • C 3 -C 1Q heteroaryl means a heteroaryl group having from 3 to 10 carbon atoms in its ring.
  • C 2 -C 1Q heteroaryl groups include, but are not limited to, 1,2,4-triazole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, pyridine, hydrazine, quinoline.
  • heterocycloalkyl denotes a monocyclic or fused saturated cyclic group containing one or more heteroatoms of N, 0 or S.
  • C 4 -C 8 heterocyclic group means a heterocyclic group having 4 to 8 carbon atoms in its ring.
  • the C 4 -C 8 heterocyclic group includes, but is not limited to, piperazino, morpholino, piperidino, pyrrolidinyl and the like.
  • C 6 -C 1Q bridged ring group means a polycyclic group having 6 to 10 carbon atoms, wherein any two rings share two carbon atoms which are not directly connected.
  • a group "covalent bond” means that the carbon atom or hetero atom attached to the two ends of the group is directly connected to form a covalent bond between the other atoms.
  • the present invention also provides a process for the preparation of the above compounds, but is not limited to the following methods:
  • Z 6 and ZZZ 9 are as described in the formula (I).
  • the starting material a and the starting material b are subjected to a substitution reaction under basic conditions to form an intermediate c, and the nitro group of the intermediate c is reduced to an amino group under the action of the insurance powder, zinc powder or palladium carbon, and the amino group of the intermediate d is 3, 3-Dimethylbutyryl chloride is reacted under basic conditions of sodium hydride, triethylamine or N,N-diisopropylethylamine to give the desired product.
  • an anthracene ring may be substituted by R 1 and R 2 , R ⁇ R 2 , Z 3 , ZZ 6 , Z
  • Z 8 and Z 9 are as defined in the formula (I).
  • Tris(diphenylmethyleneacetone)dipalladium forms a complex with 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl, and the alkalization of catalytic starting material e under basic conditions The reaction gives the desired product.
  • G is selected from C 3 -C 1Q heteroaryl, C 3 -C 6 cycloalkenyl or substituted benzocycloalkenyl, when R 14 is bromo, chloro or trifluoromethanesulfonate, R 15 is boric acid or Finacol borate group; when R 14 is a boric acid group, R 15 is bromine.
  • the raw material f and the raw material g are subjected to suzuki coupling reaction under the protection of nitrogen under the condition of potassium carbonate by bis-triphenylphosphine palladium dichloride to obtain the target product.
  • E is selected from ⁇ , ⁇ v ⁇ 3 or ⁇ z9 , z ⁇ 7 , and the anthracene ring may be substituted by R 1 and R 2 , I 1 , R 2 , Z 3 , ZZ 6 , Z
  • Z 8 and Z 9 are as defined in the formula (I).
  • the raw material a and the raw material h are subjected to a reductive amination reaction under the action of sodium triacetoxyborohydride or sodium cyanoborohydride to obtain a final product.
  • E is selected from W z- z , the E ring may be substituted by R 1 and R 2 , and the definitions of RR 2 , Z 3 , ZZ 6 , Z z ⁇ z 9 are as defined in the formula ⁇ ).
  • the starting material a and the starting material i are subjected to a substitution reaction under alkaline conditions to obtain a target product.
  • the compound of the formula (I) can be acidified using a hydrochloric acid diethyl ether solution to directly obtain the hydrochloride salt.
  • the hydrochloride salt of the compound of the formula (I) can be freed from the corresponding base by triethylamine, a saturated aqueous solution of sodium hydrogencarbonate or a certain aqueous solution of sodium hydroxide.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition which is affected by an enhancement of M-type potassium current.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of increased sensitivity to potassium channel ion flux, particularly the central nervous system Diseases in disease drugs, such as diseases or conditions that are affected by activation of voltage-gated potassium channels.
  • the disease or condition is preferably epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, stroke, ***e abuse, nicotine withdrawal, alcohol withdrawal or tinnitus.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing the ion flux in a potassium channel of a mammal, particularly a human, in particular for increasing breastfeeding The channel opening rate of the KCNQ2/3 channel in animals.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • a therapeutically effective amount may be one or more symptoms that alleviate one or more symptoms of a disease or condition in a subject, or one or more physiological or biochemical parameters associated with the disease or condition, or a cause thereof. The amount that restores normal, and/or reduces the likelihood of a disease or condition.
  • a pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the term "potassium channel modulator” as used herein refers to a compound that is capable of causing an increase in potassium channel current. It also refers to compounds that increase the KCNQ2/3 channel open rate.
  • salts which retain the biological effectiveness and properties of the parent compound, which have the desired pharmaceutical activity and which are not biologically and otherwise undesirable.
  • Such salts include:
  • a salt with an acid obtained by the reaction of a free base of a parent compound with an inorganic or organic acid
  • inorganic acids including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, organic acids including but Not limited to acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic Acid, tartaric acid;
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be tested for pharmacological activity by electrophysiological experiments, turbulence experiments, atomic absorption Rb + efflux high-throughput assays and the like.
  • Patch clamp technology known as the "gold standard” for studying ion channels, is the most important technique for ion channel functional studies.
  • the patch-clamp technique uses a micro-glass tube electrode to contact the cell membrane and docks it with an impedance of more than a gigaohm, so that the cell membrane area (membrane) that is in contact with the opening of the electrode tip is electrically separated from its surroundings, on the basis of which A fixed potential is used to detect and record the ion current of the ion channel on the diaphragm. Functional verification of KCNQ potassium channel modulators using patch clamp technique.
  • turbulence assays are widely used in high-throughput screening of potassium channel modulators.
  • the turbulence test utilizes the permeability of the KCNQ potassium channel to the cesium ion, and the opening or closing of the potassium channel is determined by detecting the concentration of the enthalpy inflow.
  • the strontium ions enter the cell from the extracellular solution, bind to the intracellular sensitizing dye, and detect the transmembrane flow of strontium ions by fluorescence signal, which is used to screen the potassium channel regulator.
  • the atomic absorption Rb + efflux assay is faster and more reliable in high-throughput screening of potassium channel modulators and has a direct reflection of ion channel activity and modulator regulation.
  • Rb + has a similar atomic size to K + , and the potassium ion channel is permeable to Rb + , and the opening or closing of the potassium channel can be determined by detecting the concentration of Rb + efflux.
  • Rb + has a specific atomic absorption at 780 nm, and the Rb + concentration can be detected by atomic absorption. Therefore, an open source or blocker for screening potassium channels can be determined by atomic absorption spectrometry using a high-throughput assay for measuring Rb + efflux.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is confirmed to have a pharmacological activity of potassium ion channel opening by electrophysiological experiments, turbulence experiments, atomic absorption Rb + efflux high-throughput assays and the like.
  • This product was synthesized from Compound 2A and sodium thiosulfate according to the preparation method of Compound 1C, 72% yield.
  • This product was synthesized from Compound 3B and sodium thiosulfate according to the preparation method of Compound 1C, 86% yield.
  • Phenyl succinic anhydride (10 g, 57 mmol) was dissolved in 1,2-dichloroethane (200 mL) and added dropwise to aluminum trichloride (17 g, 130 mmol) of 1,2-dichloromethane at 0 °C.
  • aluminum trichloride 17. g, 130 mmol
  • hexane 50 mL
  • the mixture was stirred at room temperature for 1 hour, then added with water (50 mL) at 0 ° C, and ethyl acetate (3 ⁇ 60 mL). , product as light yellow oil (8.3 g, 83% yield).
  • Lithium tetrahydrogen aluminum (0.78 g, 20.6 mmol) was dissolved in 50 mL of tetrahydrofuran. After cooling to 0 °C in ice-water bath, a solution of compound 5F (1.5 g, 9.4 mmol) in tetrahydrofuran (10 mL) was added dropwise during the dropwise addition. The internal temperature of the reaction solution does not exceed 10 V. After the addition was completed, the reaction solution was refluxed for 3 h. After dropping to room temperature, excess lithium aluminum hydride was removed using the Fieser method. The aluminum salt was removed by filtration, and the filtrate was applied to ethyl acetate (3.times.50mL), and the organic phase was evaporated to dryness to afford compound 5 g as yellow oil.
  • Tris(diphenylmethyleneacetone)dipalladium (Pd 2 (dba) 3 , 73 mg, 0.103 mmol) and B 2 -dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl ( X-phos, 98 mg, 0.206 mmol) was dissolved in 25 mL of toluene for 15 min then added compound 5G (150 mg, 1.03 mmol), N- (4-bromo-2,6-dimethylphenyl) 3-methylbutyramide (337 mg, 1.13 mmol) and t-BuOK (potassium tert-butoxide, 0.23 g, 2.06 mmol).
  • This product is synthesized from 3-fluorophenylacetic acid and ethanol according to the preparation method of compound 5B, 97% yield.
  • This product was synthesized from the crude product of Compound 6D and aluminum trichloride according to the preparation method of Compound 5A, yield 73%.
  • This product was synthesized from Compound 6E and methanol according to the preparation method of Compound 5B, 76% yield.
  • This product was synthesized from hydroxylamine hydrochloride and compound 6F according to the preparation method of compound 5C, 92% yield.
  • This product was synthesized from Compound 6H according to the preparation method of Compound 5E, with a yield of 87%.
  • This product was synthesized from Compound 61 and dicyclohexylcarbodiimide according to the preparation method of Compound 5F in 77% yield. This compound was used in the next step without purification.
  • This product was synthesized from the compound 6J according to the preparation method of the compound 5G, and the product was used in the next reaction without purification.
  • This product is synthesized from 2-fluorophenylacetic acid and ethanol according to the preparation method of compound 5B, 95% yield.
  • This product was synthesized from Compound 7A and 2-bromoacetic acid ethyl ester according to the preparation of Compound 6B, with a yield of 79%.
  • This product is synthesized from 2-fluoro-2-benzenesuccinic acid, acetyl chloride and thionyl chloride according to the preparation method of compound 6D, and the crude product is directly subjected to a step reaction.
  • This product was synthesized from Compound 7D and aluminum trichloride according to the preparation method of Compound 5A, 41% yield.
  • This product was synthesized from the compound 7E and methanol according to the preparation method of the compound 5B in a yield of 99%.
  • This product is synthesized from hydroxylamine hydrochloride and compound 7F according to the preparation method of compound 5C, and the product is directly used for the next reaction.
  • This product was synthesized from Compound 7H and potassium hydroxide according to the preparation of Compound 6C. This product was used directly in the next step without further purification.
  • This product was synthesized from Compound 71 and dicyclohexylcarbodiimide according to the preparation method of Compound 5F. This product was used for the next reaction without purification.
  • This product was synthesized from the compound 7J according to the preparation method of the compound 5G, and the product was used for the next reaction without purification.
  • This product is synthesized from 2-chloro-5-fluorophenylacetic acid and ethanol according to the preparation method of compound 5B, yield 99%.
  • This product was synthesized from Compound 8A and ethyl bromoacetate according to the preparation method of Compound 6B, yield 97%.
  • This product was synthesized from the compound 8C according to the preparation method of the compound 6D, and the product was directly used for the next reaction without purification.
  • This product was synthesized from the crude product of the compound 8D and aluminum trichloride according to the preparation method of the compound 5A, and the product was directly used for the next reaction without purification.
  • This product was synthesized from Compound 8E and methanol according to the preparation method of Compound 5B in a yield of 67%.
  • This product is synthesized from hydroxylamine hydrochloride and compound 8F according to the preparation method of compound 5C, 100% yield.
  • This product was synthesized from the compound 8H according to the preparation method of the compound 5E, and the crude product was directly used for the next reaction without purification.
  • This product is synthesized from compound 8K (300 mg, 1.83 mmol), N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide and potassium t-butoxide according to the preparation method of compound 5. , 43% yield.
  • This product was synthesized from 3-(3-methylphenyl) succinic anhydride according to the preparation method of Compound 5A.
  • This product was synthesized from Compound 9A according to the preparation method of Compound 5B.
  • This product was synthesized from Compound 9C according to the preparation method of Compound 5D.
  • This product was synthesized from Compound 9D according to the preparation method of Compound 5E.
  • This product is synthesized from the compound 9E according to the preparation method of the compound 5F.
  • This product was synthesized from the compound 9F according to the preparation method of the compound 5G.
  • This product is synthesized from 3-trifluoromethoxyphenylacetic acid and ethanol according to the preparation method of compound 5B, 96% yield.
  • This product was synthesized from Compound 10B and potassium hydroxide according to the preparation method of Compound 6C.
  • This product was synthesized from Compound 10C, acetyl chloride and thionyl chloride according to the preparation method of Compound 6D. This compound was used in the next step without purification.
  • This product was synthesized from the crude product of Compound 10D according to the preparation method of Compound 5A.
  • This product was synthesized from Compound 10E according to the preparation method of Compound 5B.
  • This product was synthesized from the compound 10F according to the preparation method of the compound 5C, with a yield of 92%.
  • This product was synthesized from Compound 10G according to the preparation method of Compound 5D.
  • This product was synthesized from the compound 10H according to the preparation method of the compound 5E.
  • This product was synthesized from Compound 101 according to the preparation method of Compound 5F.
  • This product was synthesized from Compound 10J according to the preparation method of Compound 5G.
  • This product is synthesized from 3, 5-difluorophenylacetic acid and ethanol according to the preparation method of compound 5B. The crude product is used in the next step without purification.
  • This product was synthesized from Compound 11B and potassium hydroxide according to the preparation of Compound 6C. This crude product was used in the next step without purification.
  • This product was synthesized from compound 11C, acetyl chloride and thionyl chloride according to the preparation method of compound 6D, and the crude product was used in the next reaction without purification.
  • This product was synthesized from the crude product of Compound 11D according to the preparation method of Compound 5A.
  • This product was synthesized from Compound 11E according to the preparation method of Compound 5B.
  • This product was synthesized from Compound 11F according to the preparation method of Compound 5C.
  • This product was synthesized from Compound 11G according to the preparation method of Compound 5D.
  • This product was synthesized from Compound 11H according to the preparation method of Compound 5E.
  • This product was synthesized from Compound 11J according to the preparation method of Compound 5G.
  • This product is synthesized from 2,5-difluorophenylacetic acid according to the preparation method of compound 5B.
  • This product was synthesized from Compound 12A according to the preparation method of Compound 6B.
  • This product is synthesized from the compound 12C according to the preparation method of the compound 6D, and the crude product is directly subjected to a step reaction.
  • This product is synthesized from the crude product of compound 12D according to the preparation method of compound 5A, and the yield in two steps is 90%.
  • This product was synthesized from the compound 12F according to the preparation method of the compound 5C, 95% yield.
  • This product was synthesized from the compound 12G according to the preparation method of the compound 5D, 70% yield.
  • This product was synthesized from the compound 12H according to the preparation method of the compound 5E, 88% yield.
  • This product was synthesized from Compound 121 according to the preparation method of Compound 5F.
  • This product was synthesized from Compound 12J according to the preparation method of Compound 5G.
  • This product was synthesized from 3-(3-methylphenyl) succinic anhydride according to the preparation method of Compound 5A.
  • This product was synthesized from Compound 13A according to the preparation method of Compound 5B in a yield of 67%.
  • This product was synthesized from Compound 13C according to the preparation method of Compound 5D.
  • This product was synthesized from Compound 13D according to the preparation method of Compound 5E.
  • This product was synthesized from Compound 13E according to the preparation method of Compound 5F.
  • This product was synthesized from the compound 13F according to the preparation method of the compound 5G in a yield of 79%.
  • Ethyl phenylacetate 35 g, 213 mmol was dissolved in toluene (30 mL), and a solution of potassium t-butoxide (6.2 g, 55.4 mmol) in toluene (50 mL) was added dropwise at -78 °C under nitrogen atmosphere. . After 15 minutes, a solution of 18-crown-6-ether (2.82 g, 10.7 mmol) in toluene (50 mL) was added dropwise, and after 15 minutes, a solution of methyl acrylate (1.22 mL) in toluene (5 mL) was added.
  • This product was synthesized from Compound 14A and potassium hydroxide according to the preparation method of Compound 6C, 98% yield.
  • This product is synthesized from the compound 14B, dichlorosulfoxide and acetyl chloride according to the preparation method of the compound 6D.
  • This product was synthesized from the compound 14C according to the preparation method of the compound 5A, yield 49%.
  • This product was synthesized from Compound 14D according to the method for the preparation of Compound 5B, yield 67%.
  • This product was synthesized from Compound 14E according to the method for the preparation of Compound 5C, 98% yield.
  • This product was synthesized from Compound 14F according to the preparation method of Compound 5D, 75% yield.
  • This product was synthesized from the compound 14G according to the preparation method of the compound 5E, 82% yield.
  • This product is synthesized from the compound 14H according to the preparation method of the compound 5F.
  • This product was synthesized from Compound 141 according to the preparation method of Compound 5G.
  • EK3-C2-cyano-5-fluorophenyl)acrylic acid (1.91 g, 10 mmol) was dissolved in 2:1 methanol/28% aqueous ammonia (120 mL) then Raney nickel (2.00 g) was added at room temperature under hydrogen After 16 h of reaction, the catalyst was filtered, and the solvent was evaporated to dryness to give a crude product (1.68 g, 85% yield).
  • This product consists of 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[c]aza (166 mg, 1 mmol) and N-(4-bromo-2,6-dimethyl Phenyl)-3,3-dimethylbutyramide C360 mg, 1.2 mmol) was synthesized according to the preparation method of compound 5, and reacted at 10 ° C for 4 hours. The title product was obtained (60 mg, yield 16%). MS: 383 (M+H + ).
  • This product was synthesized from 4,4-dimethylpiperidinyl-2,6-dione according to the preparation method of compound 5G in 32% yield.
  • This product was synthesized from 2-fluoroaniline and cinnamoyl chloride according to the preparation method of Compound 20A, 93% yield.
  • This product was synthesized from Compound 21A according to the preparation method of Compound 20B in a yield of 75%.
  • This product was synthesized from Compound 28B according to the preparation method of Compound 1A, 47% yield.
  • This product consists of compound 21C and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 50% yield.
  • This product consists of compound 22C and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 100% yield. MS: 383.3 (M+H + ).
  • This product consists of 3-bromoquinoline and N-( 2, 6-dimethyl-4-( 4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl)-3,3-dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 91% yield.
  • This product consists of compound 31A and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)benzene -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 77% yield. MS: 366 (M+H + ).
  • This product is synthesized from 1-tetralone according to the preparation method of compound 5C, and the yield is 100%.
  • This product was synthesized from Compound 32B according to the preparation method of Compound 5G in a yield of 81%.
  • This product is synthesized from 4,5,6,7-tetrahydrothieno[3,2- C ]pyridine and 6-chloro-2,4-dimethyl-3-nitropyridine according to the preparation method of compound 1B. The rate is 79%.
  • This product is synthesized from 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 6-chloro-2,4-dimethyl-3-nitropyridine according to the preparation method of compound 1B. The rate is 79%.
  • Embodiment 44 N-(2,6-Dimethyl-4-(l-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)phenyl) Preparation of -3,3-dimethylbutanamide
  • This product is synthesized from 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-tert-butylcarboxylate according to the preparation method of compound 44A to obtain compound 44A and compound 45A. mixture.
  • This product is synthesized from a mixture of the compound 44A and the compound 45A according to the preparation method of the compound 44B to give a mixture of the compound 44B and the compound 45B.
  • This product was synthesized from Compound 51A according to the preparation method of Compound 5G, yield 91%.
  • This product is synthesized from 3a, 4,7,7a-tetrahydro-1 ⁇ -4,7-vinylisoindole-1,3(2H)-dione according to the preparation method of compound 5G, yield 91%.
  • This product consists of ⁇ -(2,4-dimethyl-6-(3a,4,7,7a-tetrahydro-1 ⁇ -4,7-vinyltetrahydroisoindole-2(3 ⁇ )-yl) ⁇
  • the pyridin-3-yl)-3,3-dimethylbutanamide was synthesized according to the method for the preparation of compound 40C in 54% yield. MS: 370 [M+l] + .
  • This product was synthesized from Compound 57A according to the preparation of Compound 5G.
  • the product was acidified using diethyl ether aqueous hydrochloric acid to give crude compound 57B, which was used directly in the next reaction.
  • the crude compound 59A and a solution of hydrochloric acid in diethyl ether (7M, 50 mL) were stirred at room temperature for three hours. After completion of the reaction, the crude product of Compound 59B was obtained by spin-drying, and was used for the next reaction without purification.
  • This product was synthesized from Compound 59C according to the preparation method of Compound 5G, 52% yield.
  • This product is synthesized from the compound 60A according to the preparation method of the compound 59B, and the crude product is directly subjected to a step reaction.
  • This product was synthesized from the crude compound 60B according to the preparation method of compound 59C.
  • the yield in three steps was 28%.
  • This product was synthesized from Compound 60C according to the preparation method of Compound 5G, yield 52%.
  • Embodiment 6 (S)-N-(6-(hexahydropyrrole[l,2-a]pyrazine-2(IH)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Preparation of methylbutyric acid
  • This product was synthesized from (S)-octahydropyrrole [l,2-a]pyrazine and 2-chloro-4,6-dimethyl-5-nitropyridine according to the preparation method of Compound 2A, 46% yield.
  • This product consists of N-(4-(isoquinolin-3-yl) 2,6-dimethyl)-3,3-dimethylbutanamide according to the preparation method of compound 15 and stirred at room temperature for 2 h, 25% yield .
  • This product is synthesized from 3-quinoline boronic acid and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 19A.
  • the product is acidified with hydrochloric acid ethyl ether solution. Acid salt, 94% yield. MS: 347.3 (M+H + ).
  • N, N-Diisopropylethylamine (DIEA, 227 mg, 1.72 mmol) was added to N-(4-(hydroxymethyl)-2,6-dimethylphenyl)-3, 3- at 0 °C Methyl butyl amide (220 mg, 0.88 mmol) in acetonitrile solution, stirring at 0 ° C for 10 minutes, methanesulfonyl chloride (181 M /, 1.06 mmol) dissolved in 5 ml of acetonitrile, and added to the reaction solution at 0 ° C The reaction was stirred at room temperature for 1 hour. The reaction mixture was dried with EtOAc EtOAc m.
  • Tetrahydroisoquinoline and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutyramide were added to 1,2-dichloroacetamidine, and triacetyl was added at 0 °C.
  • Sodium oxyborohydride which was reacted at 25 ° C for 2 hours, quenched with ammonium chloride solution, extracted with ethyl acetate (20 mL ⁇ 3), dried over anhydrous sodium sulfate. Solid (50 mg, yield 29%). MS: 363 (M-H+).
  • This product consists of 1,2,3,4-tetrahydro-1,4-methylene isoquinoline and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutyl
  • the amide was synthesized according to the method for the preparation of compound 74 in 12% yield.
  • N-(4-Bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (3 g, 10.1 mmol) was dissolved in dry tetrahydrofuran (50 ml) under nitrogen. After cooling to -78 °C, add n-hexane solution of n-butyllithium (8.8 ml, 14.1 mmol, 1.6 mol/L), keep the temperature stable at -78 and stir for one hour, then add DMF (1.4 ml). , 18 mmol). The reaction mixture was stirred at -78 °C for one hour.
  • This product is synthesized from 8-azaspiro[4,5]nonane-7,9-dione according to the preparation method of compound 5G, 95% yield ⁇ 8-(3, 5-dimethyl-4-nitro Phenyl)-8-azaspiro[4.5]decane (compound 81B)
  • This product was synthesized from compound 81A and 4-fluoro-2,3-dimethylnitrobenzene according to the preparation method of compound 53A, and reacted at 120 ° C for 24 h, 59% yield.
  • This product was synthesized from Compound 84B according to the preparation method of Compound 83C, yield 94%.
  • This product is synthesized from compound 86C and 6-chloro-2,4-dimethyl-3-nitrobenzene according to the preparation method of compound 53 ⁇ , 40% yield.
  • This product consists of 8-aziro[4.5]olane and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutyramide according to the preparation method of compound 74, reflux 2d, 8.1 % yield.
  • This product is synthesized from 2-fluorophenylboronic acid and tert-butyl 4-(trifluoromethanesulfonate)-5,6-dihydropyridine-1(2H)-formate according to the preparation method of compound 19A, 94% Yield.
  • This product was synthesized from Compound 88B according to the preparation method of Compound 29.
  • This product is synthesized from 2-trifluoromethylphenylboronic acid and tert-butyl 4-(trifluoromethanesulfonate)-5,6-dihydropyridine-1(2H)-formate according to the preparation method of compound 19A. , 76% yield.
  • This product was synthesized from Compound 89A according to the preparation method of Compound 29B, yield 99%.
  • This product was synthesized from Compound 89B according to the method for producing Compound 29.
  • This product was synthesized from Compound 89C and 4-fluoro-2,3-dimethylnitrobenzene according to the preparation method of 53A, 4% yield.
  • This product was synthesized from Compound 89D according to the preparation method of Compound 80C.
  • This product is synthesized from 3-fluorophenylboronic acid and tert-butyl-4-trifluoromethanesulfonyl-5,6-dihydropyridine-1 (2H)-carboxylate according to the preparation method of compound 19A, 77% yield .
  • This product was synthesized from Compound 90B according to the preparation method of Compound 29, 100% yield.
  • This product is prepared from the compound 90E according to the method of the compound 80, stirring at room temperature for 1 hour, and the product is acidified with hydrochloric acid diethyl ether to give the hydrochloride salt, 99% yield. MS: 397.3 (M+H+).
  • This product is synthesized from 4-fluorobenzeneboronic acid and tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-methyl ester according to the preparation method of compound 19A. , 94% yield.
  • This product was synthesized from Compound 93 A according to the preparation method of Compound 29B, yield 99%.
  • This product was synthesized from the compound 93C according to the method for the preparation of compound 29, yield 93%.
  • This product was synthesized from compound 93C and 4-fluoro-2,6-dimethylnitrobenzene according to the preparation method of compound 53A, 46% yield.
  • This product was synthesized from Compound 93D according to the preparation method of Compound 80C, 85% yield.
  • This product is synthesized from tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carbonate and 4-chlorophenylboronic acid according to the preparation method of compound 19A. , 94% yield.
  • This product was synthesized from Compound 94A according to the preparation method of Compound 29B, yield 99%.
  • This product was synthesized from Compound 94B according to the method for the preparation of Compound 29, 90% yield.
  • This product was synthesized from Compound 94C according to the method for the preparation of Compound 53A, 30% yield.
  • This product was synthesized from Compound 94D according to the method for the preparation of Compound 1C, 84% yield.
  • tert-Butyl 4-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carbonate (Compound 95A) Preparation of tert-butyl 4-("trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carbonate and 4-trifluoromethylbenzeneboronic acid according to compound 19A Method synthesis, 73% yield.

Abstract

Disclosed is a compound as a potassium channel modulator, which is a compound of general formula (I) or a pharmaceutically acceptable salt thereof. Such compound can be used to prepare drugs for increasing the flow of ions in potassium channels in a mammal, or prepare drugs for treating diseases which are sensitive to the increase of the ion flow in potassium channels.

Description

作为钾通道调节剂的化合物 技术领域  Compound as a potassium channel regulator
本发明涉及一类调节钾通道的化合物， 该化合物对治疗和预防受钾离子通道的活性影响 的疾病和病症有效果。  The present invention relates to a class of compounds which modulate potassium channels which are effective in the treatment and prevention of diseases and conditions which are affected by the activity of potassium ion channels.
背景技术 Background technique
KCNQ 钾通道为钾离子通道超家族的重要分支， 目前共发现 KCNQ1 5 五种类型， 其基 因突变与许多遗传性疾病有关 （Jentsch Natwre ?eWe N rara'ewce, 2000 1,21-30) 。 其中， KCNQl(KvLQT)主要分布于心肌， 50% 的遗传性 LQT综合征与 KCNQ1突变有关。 KCNQ2-5 主要分布于中枢神经***、 内耳 （KCNQ4) 和肌肉组织 （KCNQ5) KCNQ2禾 B KCNQ3 是 构成神经细胞 M 型钾离子通道的分子基础， 良性家族性新生儿惊厥症（BFNC)与 KCNQ2 KCNQ3基因突变后引起的 M电流下调有关。 KCNQ4高表达于与听觉有关的神经传导通路、 神经核团及内耳毛细胞， 遗传性耳聋症 （DFNA) 与 KCNQ4基因突变有关。  The KCNQ potassium channel is an important branch of the potassium channel superfamily. Five types of KCNQ1 5 have been found, and their gene mutations are associated with many hereditary diseases (Jentsch Natwre?eWe Nrara'ewce, 2000 1, 21-30). Among them, KCNQl (KvLQT) is mainly distributed in the myocardium, and 50% of hereditary LQT syndrome is associated with KCNQ1 mutation. KCNQ2-5 is mainly distributed in the central nervous system, inner ear (KCNQ4) and muscle tissue (KCNQ5). KCNQ2 and B KCNQ3 are the molecular basis of the M-type potassium channel of nerve cells, benign familial neonatal seizures (BFNC) and KCNQ2 KCNQ3. Down-regulation of M current caused by mutation of the gene. KCNQ4 is highly expressed in auditory-related nerve conduction pathways, nucleus and inner ear hair cells, and hereditary deafness (DFNA) is associated with KCNQ4 gene mutation.
瑞替加滨化学结构为 N-2-氨基 -4-(4-氟苯甲基) -氨基甲酸乙酯， 对顽固性癫痫的部分性发 作具有显著效果， 于 2011年 6月被美国 FDA批准上市， 作为辅助用药治疗成人癫痫部分性 发作。 瑞替加滨对 KCNQ钾通道具有开放作用， 能够有效激活 M型钾电流， 降低神经元的 兴奋性， 具有广谱和有效的抗惊厥作用， 在遗传性癫痫和不同的点燃模型中均有效， 对最大 电惊厥 （MES) 、 由戊四唑 （PTZ) N-甲基 -D-天冬氨酸 （NMDA) 、 印防己毒素、 红藻氨 酸盐、青霉素、钾盐镁矾、音原性刺激诱发的啮齿类动物的发作均表现出抗惊厥活性（Luszczki JJ. Pharmacol Rep, 2009, 61, 197-216)  The chemical structure of retigabine is N-2-amino-4-(4-fluorobenzyl)-carbamic acid ethyl ester, which has a significant effect on partial seizures of intractable epilepsy. It was approved by the US FDA in June 2011. Listed as adjunctive medication for partial seizures in adult epilepsy. Retigabine has an open function on KCNQ potassium channel, which can effectively activate M-type potassium current and reduce neuron excitability. It has broad-spectrum and effective anticonvulsant effect, and is effective in hereditary epilepsy and different ignition models. For maximal electroconvulsive (MES), by pentylenetetrazol (PTZ) N-methyl-D-aspartate (NMDA), indomethacin, kainate, penicillin, potassium magnesium, pyrogenicity Stimulation-induced rodent seizures exhibit anticonvulsant activity (Luszczki JJ. Pharmacol Rep, 2009, 61, 197-216)
瑞替加滨对神经性疼痛的动物模型表现出有益效果 （Blackbum-Munro et al, European Journal of Pharmacology, 2003, 460, 109-116) ， 提示 KCNQ钾通道开放剂可用于治疗疼痛性 疾病。 KCNQ2 5钾通道 R A在三叉神经节、 背根神经节和三叉神经尾状核的表达意味着这 些通道开放剂可能影响偏头痛的感觉过程 ( Goldstein et al, Society for Neuroscience Abstracts, 2003,53) 。 体内外研究表明， 瑞替加滨对焦虑、 脑卒中、 神经变性疾病等也具有潜在的治疗 效果。 瑞替加滨的成功上市和体内体外的优异表现证明 KCNQ钾通道作为药物靶点具有重要意 义。 KCNQ钾通道开放剂成为抗癫痫药物研究的新方向， 同时， 由于 KCNQ钾通道生理功能 广泛， 其开放剂也具有十分广阔的应用前景。 Retigabine has a beneficial effect on animal models of neuropathic pain (Blackbum-Munro et al, European Journal of Pharmacology, 2003, 460, 109-116), suggesting that KCNQ potassium channel openers can be used to treat painful diseases. The expression of KCNQ2 5 potassium channel RA in the trigeminal ganglion, dorsal root ganglia, and trigeminal caudate nucleus means that these channel openers may affect the sensory process of migraine (Goldstein et al, Society for Neuroscience Abstracts, 2003, 53). In vitro and in vivo studies have shown that retigabine also has potential therapeutic effects on anxiety, stroke, and neurodegenerative diseases. The successful marketing of retigabine and its excellent performance in vitro and in vivo demonstrate the importance of KCNQ potassium channel as a drug target. KCNQ potassium channel opener has become a new direction for antiepileptic drug research. At the same time, due to the wide physiological function of KCNQ potassium channel, its open agent also has a very broad application prospect.
发明内容 Summary of the invention
本发明的目的是提供一类具有调节钾通道功能的化合物。  It is an object of the present invention to provide a class of compounds having the function of modulating potassium channels.
本发明的另一目的是提供一种上述化合物在医药方面的用途。  Another object of the present invention is to provide a pharmaceutical use of the above compounds.
本发明的目的可以通过以下措施达到：  The object of the invention can be achieved by the following measures:
式（I)化合物或其药学上可接受
Figure imgf000004_0001
Figure imgf000004_0002
或 C3-C1Q杂芳基， 且 A环被 R1和 R2取代； 其中， 当 A为 C3-C1Q杂芳基时， A不为吡咯基和苯并咪唑基； a compound of formula (I) or a pharmaceutically acceptable compound thereof
Figure imgf000004_0001
Figure imgf000004_0002
Or a C 3 -C 1Q heteroaryl group, and the A ring is substituted by R 1 and R 2 ; wherein, when A is a C 3 -C 1Q heteroaryl group, A is not a pyrrolyl group and a benzimidazolyl group;
R1和 R2各自独立地选自氢、 卤素、氰基、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6 环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C10 芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 CrC6烷基、 CrC6卤代烷基、 CrC6烷氧基、 CrC6卤代烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基的取 代基所取代； R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 10 aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C Substituted with a 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group;
或者， R1和 R2除以上给定含义之外， 当 R1与 R2连接在相邻的碳原子上时， R1和 R2与 它们所结合的碳原子共同形成五元或六元饱和碳环； 当 R1和 R2连接在同一个碳原子上时， R1和 R2与它们所结合的碳原子共同形成羰基、 C3-C6环烷基或者苯并 C3-C6环烷基； Alternatively, R 1 and R 2 in addition to the above given meanings, when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 together with the carbon atom to which they are bonded form a five or six member a saturated carbocyclic ring; when R 1 and R 2 are bonded to the same carbon atom, R 1 and R 2 together with the carbon atom to which they are bonded form a carbonyl group, a C 3 -C 6 cycloalkyl group or a benzo C 3 -C 6 cycloalkyl;
R3选自 CrC6烷基、 C3-C6环烷基、 C6-C8桥环基、金刚烷基、 C6-C1Q芳基、 C3-C1Q杂芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或 C2-C6块基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 crc6烷基、 c3-c6环烷基、 c6-c1Q芳基、 crc6 ^i代烷基、 d-c6烷氧基、 d-C6氨基烷基或 d-C6 ^代烷氧基的取代基所取代； R4和 R5各自独立地为氢、 卤素、氰基、 d-C6烷基、 d-C6烷氧基、 d-C6氨基烷基、 Ci-C 烷氨基、 crc6卤代烷基或 crc6卤代烷氧基; R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged cycloalkyl, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q aryl, heteroaryl, C 4 -C 8 heterocycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl or C 2 -C 6 block, and one or more selected from hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, c r c 6 alkyl, c 3 -c 6 cycloalkyl, c 6 -c 1Q aryl, c r c 6 ^i alkyl, dc 6 alkoxy, Substituted by a substituent of dC 6 aminoalkyl or dC 6 ^ alkoxy; R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C alkylamino, c r c 6 haloalkyl or c r c 6 Haloalkoxy;
■Z2 λ' ■Z 2 λ'
X和 Y各自独立地为 CH或 N， 其中， 当 A为 z4vz3 时， X和 Y为 CH; X and Y are each independently CH or N, wherein, when A is z4 v z3 , X and Y are CH;
Z1选自共价键或 d-C6亚烷基，其中所述 d-C6亚烷基可被一个或多个选自氢或 d-C6烷 基的取代基取代； Z 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
Z2和 Z5各自独立地为 CH或者 N; Z 2 and Z 5 are each independently CH or N;
Z3和 Z4各自独立地为 C、 CH、 CH2、 N、 NH或者共价键， 其中， Z2和 Z3不同时含有 N; Z6、 Z7和 Z8各自独立地选自 CH2、 （CH2)2、 NH、 NCH3、 NCH2CH3或共价键， 其中 Z5 和 Z6、 Z5和 Z7、 Z7和 Z8、 Z8和 Z9不同时含有 N， Z6、 Z7和 Z8不同时为共价键； Z 3 and Z 4 are each independently C, CH, CH 2 , N, NH or a covalent bond, wherein Z 2 and Z 3 do not simultaneously contain N; Z 6 , Z 7 and Z 8 are each independently selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond, wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N , Z 6 , Z 7 and Z 8 are not covalent bonds at the same time;
Z N、 C或 CH;  Z N, C or CH;
p为 1或 2;  p is 1 or 2;
n为 0-6的整数；  n is an integer from 0 to 6;
B选自 C3-C6环烯基、 C3-C6环烷基、 C6-C1Q芳基、 C2-C1Q杂芳基、 C4-C8杂环烷基或 C6-C10 桥环基； 其中， B环与含有 Ζ 人人 / 人人 /B is selected from C 3 -C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C 2 -C 1Q heteroaryl, C 4 -C 8 heterocycloalkyl or C 6 -C 10 bridge ring base; Among them, B ring and contains Ζ everyone / everyone /
Figure imgf000005_0001
Figure imgf000005_0001
在本发明的一种优选方案中：  In a preferred embodiment of the invention:
一类化合物或其药学上可接受 其化合物具有式 （Π) 结构， 其中:
Figure imgf000005_0002
A class of compounds or pharmaceutically acceptable compounds thereof having the formula (Π), wherein:
Figure imgf000005_0002
(II)  (II)
ρ为 1或 2;  ρ is 1 or 2;
η为 0或 1 ;  η is 0 or 1 ;
X和 Υ各自独立地为 CH或 Ν;  X and Υ are each independently CH or Ν;
Ζ1选自共价键或 CrC6亚烷基，其中所述 CrC6亚烷基可被一个或多个选自氢或 CrC6烷 基的取代基取代； R3选自 d-C6烷基、 C3-C6环烷基、 C6-C8桥环基、金刚烷基、 C6-C1Q芳基、 C3-C1Q杂芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或 C2-C6块基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 d-C6烷基、 C3-C6环烷基、 C6-C1Q芳基、 d-C6 ^代烷基、 6烷氧基、 CrC6氨基烷基或 CrC6 ^代烷氧基的取代基所取代； Ζ 1 selected from a covalent bond or C r C 6 alkylene, wherein said C r C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or C r C 6 alkyl substituents; R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl, C 4 a -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 block group, and one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Base, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, dC 6 ^alkyl, 6 alkoxy, C r C 6 aminoalkyl or Substituted by a substituent of C r C 6 ^ alkoxy;
R4和 R5各自独立地为氢、 卤素、氰基、 d-C6烷基、 d-C6烷氧基、 d-C6氨基烷基、 Ci-C6 烷氨基、 CrC6卤代烷基或 CrC6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
R6和 R7各自独立地选自氢、 卤素、 d-C6烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯 基、 -C j烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 -¾杂环烷基， 其中所述 CrC6 烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 ¾ 8杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 d-C6烷基、 d-C6卤代烷基、 d-C6烷氧基、 d-C6卤代烷氧基、 C3-C6环烷基、 C3-C6 环烯基、 c2-c6链烯基、 c2-c6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基的取代基所 取代。 R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, dC 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, -C j alkenyl, C block basis 2 -C 6, C 6 -C 1Q aryl, C 3 -C 1Q -¾ heteroaryl or heterocycloalkyl, wherein said C r C 6 alkyl, dC 6 alkoxy, C 3 - C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or 3⁄4 The heterocycloalkyl group is optionally independently selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, dC 6 alkyl, dC 6 haloalkyl, dC 6 alkoxy, dC 6 haloalkoxy , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, c 2 -c 6 alkenyl, c 2 -c 6 block, C 6 -C 1Q aryl, C 3 -C 1Q The substituent of the heteroaryl or c 4 -c 8 heterocycloalkyl group is substituted.
优选地， 式 II中的 Z1为 CH2。 Preferably, Z 1 in formula II is CH 2 .
优选地， 式 Π中的 R3选自 CrC6烷基、 C3-C6环烷基或 C6-C1()芳基， 并且被一个或多个 选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代。 更优选地， R3为甲基、 乙基、 正丙 基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环己基、 环戊基、 环丁基或苯基。 Preferably, in formula Π R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1 () aryl, and substituted with one or more substituents selected from hydrogen, halogen, cyano Substituted by a substituent of a nitro group, an amino group or a hydroxy group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane Base or phenyl.
优选地， 式 Π中的 R4和 R5各自独立地为 CrC6烷基。 更优选地， R4和 R5各自独立地为 甲基或乙基。 Preferably, R 4 and R 5 in the formula are each independently C r C 6 alkyl. More preferably, R 4 and R 5 are each independently methyl or ethyl.
优选地， 式 Π中的 R6和 R7各自独立地选自氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 C2-C6链烯基、 C2-C6块基， 其中所述 d-C6烷基、 d-C6烷氧基、 C2-C6链烯基、 C2-C6块基独 立可选地被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代。 更优选地， R6和 R7各自独立地为氢、 氟、 氯、 溴、 甲基、 甲氧基、 三氟甲基或三氟甲氧基。 Preferably, R 6 and R 7 in the formula are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkenyl, C 2 a -C 6 block group, wherein the dC 6 alkyl group, the dC 6 alkoxy group, the C 2 -C 6 alkenyl group, the C 2 -C 6 block group are independently optionally one or more selected from the group consisting of hydrogen and halogen Substituted by a substituent of a cyano group, a nitro group, an amino group or a hydroxyl group. More preferably, R 6 and R 7 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
在本发明的另一种优选方案中：  In another preferred embodiment of the invention:
一类化合物或其药学上可接受的盐， 该化合物具有式 （ΠΙ ) 结构， 其中：
Figure imgf000006_0001
A compound or a pharmaceutically acceptable salt thereof, which has the formula (ΠΙ), wherein:
Figure imgf000006_0001
(ΠΙ) z1选自共价键或 d-C6亚烷基，其中所述 d-C6亚烷基可被一个或多个选自氢或 d-C6烷 基的取代基取代； (ΠΙ) z 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
Z2为 CH或者 N; Z 2 is CH or N;
Z3和 Z4各自独立地为 C、 CH、 CH2、 N、 NH或者共价键， 其中， Z2和 Z3不同时含有 N; n为 0或 1 ; Z 3 and Z 4 are each independently C, CH, CH 2 , N, NH or a covalent bond, wherein Z 2 and Z 3 do not simultaneously contain N; n is 0 or 1;
R3选自 CrC6烷基、 C3-C6环烷基、 C6-C8桥环基、金刚烷基、 C6-C1Q芳基、 C3-C1Q杂芳基、 C4-C8杂环烷基、 c3-c6环烯基、 c2-c6链烯基或 c2-c6块基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 crc6烷基、 c3-c6环烷基、 c6-c1Q芳基、 crc6 ^i代烷基、 d-c6烷氧基、 d-C6氨基烷基或 d-C6 ^代烷氧基的取代基所取代； R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged cycloalkyl, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q aryl, heteroaryl, a C 4 -C 8 heterocycloalkyl, c 3 -c 6 cycloalkenyl, c 2 -c 6 alkenyl or c 2 -c 6 block, and one or more selected from the group consisting of hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, c r c 6 alkyl, c 3 -c 6 cycloalkyl, c 6 -c 1Q aryl, c r c 6 ^i alkyl, dc 6 alkoxy, Substituted by a substituent of dC 6 aminoalkyl or dC 6 ^ alkoxy;
R4和 R5各自独立地为氢、 卤素、氰基、 CrC6烷基、 CrC6烷氧基、 CrC6氨基烷基、 C C6 烷氨基、 d-C6卤代烷基或 d-C6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C r C 6 aminoalkyl, CC 6 alkylamino, dC 6 haloalkyl or dC 6 haloalkoxy;
R8和 R9各自独立地选自氢、氰基、 卤素、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6 环烯基、 c2-c6链烯基、 c2-c6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基， 其中所述 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C10 芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 CrC6烷基、 CrC6卤代烷基、 CrC6烷氧基、 CrC6卤代烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基的取 代基所取代； R 8 and R 9 are each independently selected from the group consisting of hydrogen, cyano, halogen, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, a c 2 -c 6 alkenyl group, a c 2 -c 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a c 4 -c 8 heterocycloalkyl group, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 10 aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C Substituted with a 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group;
或者除以上给定含义之外， 当 R8和 R9连接在同一个碳原子上时， R8和 R9与它们所结合 的碳原子共同形成羰基、 c3-c6环烷基或者苯并 c3-c6环烷基。 Or in addition to the above given meanings, when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a c 3 -c 6 cycloalkyl group or a benzene group. And c 3 -c 6 cycloalkyl.
优选地， 式 III中的 R3选自 crc6烷基、 c3-c6环烷基或 c6-c1()芳基， 并且被一个或多个 选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代。 更优选地， R3为甲基、 乙基、 正丙 基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环己基、 环戊基、 环丁基或苯基。 Preferably, R 3 in formula III is selected from c r c 6 alkyl, c 3 -c 6 cycloalkyl or c 6 -c 1() aryl, and is selected from one or more selected from the group consisting of hydrogen, halogen, cyanide Substituted by a substituent of a nitro group, an amino group or a hydroxy group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane Base or phenyl.
优选地， 式 III中的 R4和 R5各自独立地为 CrC6烷基。 更优选地， R4和 R5各自独立地 为甲基或乙基。 Preferably, R 4 and R 5 in formula III are each independently C r C 6 alkyl. More preferably, R 4 and R 5 are each independently methyl or ethyl.
优选地， 式 ΠΙ中的 R8和 R9各自独立地选自氢、 卤素、氰基、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 d-C6 烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环 烷基独立可选地被一个或多个选自氢、 卤素、 d-C6烷基、 d-C6卤代烷基、 d-C6烷氧基、 C C6卤代烷氧基的取代基取代。 或者除以上给定含义之外， 当 R8和 R9连接在同一个碳原子 上时， R8和 R9与它们所结合的碳原子共同形成羰基、 C3-C6环烷基或者苯并 C3-C6环烷基。 更优选地， R8和 R9各自独立地为氢、 氟、 氯、 溴、 甲基、 甲氧基、 三氟甲基、 三氟甲氧基、 苯基、 2-吡啶基、 3-吡啶基、 4-吡啶基、 吡咯烷基、 哌啶基、 N-吗啉基， 其中所述的苯基独立 可选地被一个或多个选自氢、 卤素、 CrC3烷基、 CrC3卤代烷基、 CrC3烷氧基、 CrC3卤代 烷氧基的取代基取代； 或者除以上给定含义之外， 当 R8和 R9连接在同一个碳原子上时， R8 和 R9与它们所结合的碳原子共同形成羰基、 环丙烷基、 环戊烷基、 环己烷基或者苯并环戊烷 基。 Preferably, R 8 and R 9 in the formula are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 a -C 6 cycloalkenyl group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group, wherein the dC 6 alkyl group, C r C 6 alkoxy group, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, optionally independently Or a plurality of substituents selected from the group consisting of hydrogen, halogen, dC 6 alkyl, dC 6 haloalkyl, dC 6 alkoxy, CC 6 haloalkoxy. Or in addition to the above given meaning, when R 8 and R 9 are attached to the same carbon atom In the above, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a C 3 -C 6 cycloalkyl group or a benzo C 3 -C 6 cycloalkyl group. More preferably, R 8 and R 9 are each independently hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl, 2-pyridyl, 3-pyridine group, 4-pyridyl, pyrrolidinyl, piperidinyl, N- morpholinyl, wherein said phenyl is optionally independently substituted with one or more substituents selected from hydrogen, halo, C r C 3 alkyl, C Substituting a substituent of r C 3 haloalkyl, C r C 3 alkoxy, C r C 3 haloalkoxy; or, in addition to the above given meaning, when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexane group or a benzocyclopentanyl group.
优选地， 式 III中的 Z1为 CH2。 Preferably, Z 1 in formula III is CH 2 .
优选地， 式 III中的 Z2、 Z3和 Z4至少有一个基团中含有 N; 进一步优选地， 含 Z2、 Z3 和 Z4的环状基团为哌啶基、 吡咯烷基或哌嗪基。 Preferably, Z 2 , Z 3 and Z 4 in the formula III contain N in at least one group; further preferably, the cyclic group containing Z 2 , Z 3 and Z 4 is piperidinyl, pyrrolidinyl Or piperazinyl.
在本发明的另一种优选方案中：  In another preferred embodiment of the invention:
一类化合物或其药学上可接 该化合物具有式 （IV) 结构， 其中：
Figure imgf000008_0001
A class of compounds or pharmaceutically acceptable compounds thereof having the structure of formula (IV) wherein:
Figure imgf000008_0001
X和 Y各自独立地为 CH或 N;  X and Y are each independently CH or N;
Z1选自共价键或 d-C6亚烷基，其中所述 d-C6亚烷基可被一个或多个选自氢或 d-C6烷 基的取代基取代； Z 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
R3选自 d-C6烷基、 C3-C6环烷基、 C6-C8桥环基、金刚烷基、 C6-C1Q芳基、 C3-C1Q杂芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或 C2-C6块基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 d-C6烷基、 C3-C6环烷基、 C6-C1Q芳基、 d-C6 ^代烷基、 6烷氧基、 CrC6氨基烷基或 CrC6 ^代烷氧基的取代基所取代； R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl, C 4 a -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 block group, and one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Base, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, dC 6 ^alkyl, 6 alkoxy, C r C 6 aminoalkyl or Substituted by a substituent of C r C 6 ^ alkoxy;
R4和 R5各自独立地为氢、 卤素、氰基、 d-C6烷基、 d-C6烷氧基、 d-C6氨基烷基、 Ci-C6 烷氨基、 CrC6卤代烷基或 CrC6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
Z5为 N或 CH; Z 5 is N or CH;
Z6、 Z7和 Z8各自独立地选自 CH2、 （CH2)2、 NH、 NCH3、 NCH2CH3或共价键， 其中 Z5 和 Z6、 Z5和 Z7、 Z7和 Z8、 Z8和 Z9不同时含有 N， Z6、 Z7和 Z8不同时为共价键； Z 6 , Z 7 and Z 8 are each independently selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond, wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N, Z 6 , Z 7 and Z 8 are not simultaneously covalent bonds;
Z N、 C或 CH;  Z N, C or CH;
m为 1-6的整数；  m is an integer from 1-6;
n为 0或 1 ; B选自 C3-C6环烯基、 C3-C6环烷基、 C6-C1Q芳基、 C2-C1Q杂芳基、 C4-C8杂环烷基或 C6-C 桥环基； 其中， B环与含有 Ζδ、n is 0 or 1; B is selected from C 3 -C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C 2 -C 1Q heteroaryl, C 4 -C 8 heterocycloalkyl or C 6 -C bridge ring base; wherein, B ring and containing Ζ δ ,
, ^^ 、 N
Figure imgf000009_0001
, ^^ , N
Figure imgf000009_0001
R1Q和 R11各自独立地选自氢、 氰基、 卤素、 d-C6烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其 中所述 d-C6烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 d-C6烷基、 d-C6卤代烷基、 d-C6烷氧基、 d-C6卤代烷氧基、 C3-C6 环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环 烷基的取代基所取代。 R 1Q and R 11 are each independently selected from the group consisting of hydrogen, cyano, halogen, dC 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said dC 6 alkyl, dC 6 Alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 - The C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl group is optionally independently selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, dC 6 alkyl, dC 6 haloalkyl, dC 6 alkoxy, dC 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - Substituted by a C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group.
优选地， 式 IV中的 R3选自 CrC6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C10 芳基、 C3-C1Q杂芳基、 c4-c8杂环烷基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 CrC3烷基、 CrC3卤代烷基、 CrC3烷氧基、 CrC3氨基烷基或 CrC3卤代烷氧 基的取代基所取代。 更优选地， R3为甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁 基、 叔丁基、 环丙基、 环己基、 环戊基、 环丁基、 苯基、 金刚烷基、 2-呋喃基、 吡咯烷基、 吡咯烷酮基或卜 ^， 其中环丙基、 环己基、 环戊基、 环丁基、 苯基、 2-呋喃基、 吡咯烷基 独立可选的被一个或多个选自氟、 氯、 溴、 甲基、 甲氧基、 三氟甲基、 三氟甲氧基、 氨基甲 基的取代基取代。 Preferably, R 3 in formula IV is selected from the group consisting of C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 10 aryl, C 3 -C 1Qheteroaryl , c 4 -c 8 heterocycloalkyl, and one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carbonyl, C r C 3 alkyl, C r Substituted by a C 3 haloalkyl, C r C 3 alkoxy, C r C 3 aminoalkyl or C r C 3 haloalkoxy group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane a phenyl group, an adamantyl group, a 2-furyl group, a pyrrolidinyl group, a pyrrolidinyl group or a cyclopropyl group, wherein a cyclopropyl group, a cyclohexyl group, a cyclopentyl group, a cyclobutyl group, a phenyl group, a 2-furyl group, a pyrrolidine group The radicals are independently optionally substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, aminomethyl.
优选地， 式 IV中的 Z1选自共价键或 d-C3亚烷基， 其中所述 d-C3亚烷基可被一个或多 个选自氢或 crc3烷基的取代基取代。 Preferably, Z 1 in formula IV is selected from a covalent bond or a dC 3 alkylene group, wherein the dC 3 alkylene group may be substituted with one or more substituents selected from hydrogen or c r c 3 alkyl.
优选地， 式 IV中的 R4和 R5各自独立地为氢、 卤素、 氰基、 d-C3烷基、 d-C3烷氧基、 CrC3氨基烷基、 CrC3烷氨基或 CrC6卤代烷氧基； R4和 R5各自独立地为氢、 氟、 氯、 溴、 甲基、 乙基、 三氟甲基、 甲氧基或三氟甲氧基。 Preferably, R 4 and R 5 in formula IV are each independently hydrogen, halogen, cyano, dC 3 alkyl, dC 3 alkoxy, C r C 3 aminoalkyl, C r C 3 alkylamino or C r C 6 haloalkoxy; R 4 and R 5 are each independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy or trifluoromethoxy.
优选地， 式 IV中的 R1Q和 R11各自独立地选自氢、 氰基、 卤素、 CrC6烷基、 CrC6烷氧 基， 其中所述 d-C6烷基、 d-C6烷氧基独立可选地被一个或多个卤素取代。 更优选地， R1Q 和 R11各自独立地为氢、 氟、 氯、 溴、 甲基、 乙基、 三氟甲基或氰基。
Figure imgf000010_0001
其中上述优选 Β基团的右侧两个连接键连接式 (IV)结构中与 Β相邻的 ， 实际上 构成两环骈合的结构。 Preferably, R 1Q and R 11 in formula IV are each independently selected from the group consisting of hydrogen, cyano, halogen, C r C 6 alkyl, C r C 6 alkoxy, wherein said dC 6 alkyl, dC 6 alkane The oxy group is optionally substituted by one or more halogens. More preferably, R 1Q and R 11 are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or cyano.
Figure imgf000010_0001
Wherein the two adjacent linking bonds of the above preferred fluorene group are adjacent to the fluorene in the structure of the formula (IV), and actually constitute a structure in which the two rings are bonded.
优选地， 式 IV中的 Ζ5为 Ν或 CH; Ζ6选自 CH2、 （CH2)2、 NH、 NCH3、 NCH2CH3或共 价键； Z7选自 CH2、 (CH2)2, NH或共价键； 其中 Z6和 Z7不同时为共价键； Z8选自 (CH2)2、 CH2或 NH; Z N、 C或 CH; 其中 Z5和 Z6、 Z5和 Z7、 Z7和 Z8、 Z8和 Z9中不同时含有 N。 Preferably, Ζ 5 in formula IV is ruthenium or CH; Ζ 6 is selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond; Z 7 is selected from CH 2 , (CH) 2 ) 2 , NH or a covalent bond; wherein Z 6 and Z 7 are not simultaneously a covalent bond; Z 8 is selected from (CH 2 ) 2 , CH 2 or NH; ZN, C or CH; wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N.
优选地， 式 IV中的含 Z5、 Z Z Z8和 Z9的环状基团 （不包括环 B ) 为哌啶基、 N-甲 基哌啶基、 N-乙基哌啶基、 环己基、 四氢吡咯基、 六氢氮杂卓基或哌嗪基。 Preferably, the cyclic group (excluding ring B) containing Z 5 , ZZZ 8 and Z 9 in formula IV is piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, cyclohexyl , tetrahydropyrrolyl, hexahydroazepine or piperazinyl.
优选地， 式 IV结构为以下组合， X和 Y为 CH， Z1为 ， R3为叔丁基， R4和 R5为 甲基， Z5为 N， Z6、 Z7和 Z8为 CH2， Z9为 C， n为 0， B为
Figure imgf000010_0002
R1Q为 H， R11为氟、 氯、 溴或甲基。 Preferably, the structure of formula IV is the combination, X and Y are CH, Z 1 is, R 3 is tert-butyl, R 4 and R 5 are methyl, Z 5 is N, Z 6 , Z 7 and Z 8 are CH 2 , Z 9 is C, n is 0, B is
Figure imgf000010_0002
R 1Q is H, and R 11 is fluorine, chlorine, bromine or methyl.
优选地， 式 IV结构为以下组合， X和 Y为 CH， Z1为亚甲基， R3 基， R4和 R5为 甲基， Z5为 N， Z6为共价键， Z7和 Z8为 (CH2)2， Z9为 C， n为 0， B为
Figure imgf000010_0003
Preferably, the structure of formula IV is the combination, X and Y are CH, Z 1 is methylene, R 3 is based, R 4 and R 5 are methyl, Z 5 is N, Z 6 is a covalent bond, Z 7 And Z 8 is (CH 2 ) 2 , Z 9 is C, n is 0, and B is
Figure imgf000010_0003
为氟、 氯、 溴或甲基。 It is fluorine, chlorine, bromine or methyl.
在本发明的另一种优选方案中：  In another preferred embodiment of the invention:
一类化合物或其药学上可接受的盐， （V) 结构， 其中：  a compound or a pharmaceutically acceptable salt thereof, (V) structure, wherein:
Figure imgf000010_0004
Figure imgf000010_0004
X和 Υ各自独立地为 CH或 Ν;  X and Υ are each independently CH or Ν;
Ζ1选自共价键或 d-C6亚烷基，其中所述 d-C6亚烷基可被一个或多个选自氢或 d-C6烷 基的取代基取代； Ζ 1 is selected from a covalent bond or a dC 6 alkylene group, wherein the dC 6 alkylene group may be substituted with one or more substituents selected from hydrogen or dC 6 alkyl;
R3选自 d-C6烷基、 C3-C6环烷基、 C6-C8桥环基、金刚烷基、 C6-C1Q芳基、 C3-C1Q杂芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或 C2-C6块基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 d-C6烷基、 C3-C6环烷基、 C6-C1Q芳基、 d-C6 ^代烷基、 6烷氧基、 CrC6氨基烷基或 CrC6 ^代烷氧基的取代基所取代； R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl, C 4 a -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 block group, and one or more selected from the group consisting of hydrogen, halogen, Cyano, nitro, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, dC 6 ^alkyl, 6 alkoxy, C r C 6 a substituted aminoalkyl or C r C 6 ^ alkoxy group substituted by the group;
R4和 R5各自独立地为氢、 卤素、氰基、 d-C6烷基、 d-C6烷氧基、 d-C6氨基烷基、 Ci-C6 烷氨基、 CrC6卤代烷基或 CrC6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, dC 6 aminoalkyl, Ci-C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
D为 C3-C1Q杂芳基， 其中， D不为吡咯基和苯并咪唑基； D is a C 3 -C 1Q heteroaryl group, wherein D is not a pyrrolyl group and a benzimidazolyl group;
R12和 R13各自独立地选自氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其 中所述 crc6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 CrC6烷基、 CrC6卤代烷基、 CrC6烷氧基、 CrC6卤代烷氧基、 C3-C6 环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环 烷基的取代基所取代； R 12 and R 13 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said c r c 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 1Q aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C Substituted with a 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group;
或者相邻的 R12和 R13与 D基团上的环原子共同形成三至六元饱和碳环。 Alternatively, adjacent R 12 and R 13 together with a ring atom on the D group form a three to six membered saturated carbocyclic ring.
优选地， 式 V中的 R3选自 CrC6烷基、 C3-C6环烷基或 C6-C1Q芳基， 并且被一个或多个 选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代。 更优选地， R3为甲基、 乙基、 正丙 基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环己基、 环戊基、 环丁基或苯基。 Preferably, in formula V R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1Q aryl, and substituted with one or more substituents selected from hydrogen, halo, cyano, Substituted by a substituent of a nitro group, an amino group or a hydroxyl group. More preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutane Base or phenyl.
优选地， 式 V中的 X和 Y各自独立地为 CH。  Preferably, X and Y in formula V are each independently CH.
优选地， 式 V中的 Z1为 CH2; Preferably, Z 1 in formula V is CH 2 ;
优选地， 式 V中的 R4和 R5各自独立地为 d-C6烷基。 更优选地， R4和 R5各自独立地为 甲基或乙基。 Preferably, R 4 and R 5 in formula V are each independently dC 6 alkyl. More preferably, R 4 and R 5 are each independently methyl or ethyl.
优选地， 式 V中的 R12和 R13各自独立地选自氢、 卤素、 氰基、 d-C6烷基、 d-C6烷氧 基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 Ci-C6院基、 Ci-Ce院氧基、 C3-C6环院基、 C3-C6环;希基、 C6-CKJ芳基、 Cg-do杂芳基或 C4-Cs 杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰基、 CrC6烷基、 CrC6卤代烷基、 CrC6 烷氧基、 d-C6卤代烷氧基的取代基取代； 或者相邻的 R12和 R13与 D基团上的环原子共同形 成五元或六元饱和碳环。 更优选地， R12和 R13各自独立地为氢、 氰基、 氟、 氯、 溴、 甲基或 三氟甲基， 或者相邻的 R12和 R13与 D基团上的环原子共同形成五元或六元饱和碳环， 如环 戊烷或环己烷。 P O 2014/048165 优选地，式 V中的 D选自
Figure imgf000012_0001
Preferably, R 12 and R 13 in formula V are each independently selected from the group consisting of hydrogen, halogen, cyano, dC 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 ring Alkenyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said Ci-C 6 moieties, Ci-Ce alkoxy, C 3 - a C 6 ring-based, C 3 -C 6 ring; Hirsch, C 6 -CKJ aryl, Cg-do heteroaryl or C 4 -Cs heterocycloalkyl optionally independently selected from one or more selected from hydrogen Substituted by halogen, cyano, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, dC 6 haloalkoxy; or adjacent R 12 and R 13 and D The ring atoms on the group together form a five- or six-membered saturated carbocyclic ring. More preferably, R 12 and R 13 are each independently hydrogen, cyano, fluoro, chloro, bromo, methyl or trifluoromethyl, or the adjacent R 12 and R 13 are bonded together with a ring atom on the D group. A five- or six-membered saturated carbocyclic ring is formed, such as cyclopentane or cyclohexane. PO 2014/048165 Preferably, D in formula V is selected from
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本发明中的术语除特别说明外， 一般具有如下的含义。  The terminology in the present invention generally has the following meanings unless otherwise specified.
术语"烷基"表示具有所述数目之碳原子的直链或支链饱和烃基。术语" crc6烷基"是指具 有 1-6个碳原子的直链或支链饱和烃基。 d-C6烷基包括但不限于甲基、 乙基、 正丙基、 异丙 基、 正丁基、 异丁基、 叔丁基、 正戊基、 异戊基、 新戊基、 正己基、 异己基、 2，2-二甲基丁基 和 2，3-二甲基丁基等。 术语 "d-C3烷基"是指具有 1-3个碳原子的直链或支链饱和烃基。 The term "alkyl" denotes a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms. The term "c r c 6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. dC 6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, dissident Base, 2,2-dimethylbutyl and 2,3-dimethylbutyl and the like. The term "dC 3 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms.
术语 "d_6亚烷基"表示具有 1-6个碳原子的通过从直链或支链的饱和烃除去两个氢原子 衍生得到的饱和二价烃基， 包括但不限于亚甲基、 亚乙基、 亚异丙基等。 The term "d- 6 alkylene" denotes a saturated divalent hydrocarbon radical having from 1 to 6 carbon atoms which is derived by the removal of two hydrogen atoms from a linear or branched saturated hydrocarbon, including but not limited to methylene, ethylene Base, isopropylidene, etc.
术语"烷氧基 "表示 0-烷基。 术语" CrC6烷氧基 "是指具有 0- C C6烷基。 The term "alkoxy" denotes 0-alkyl. The term "C r C 6 alkoxy" refers to an alkyl group having 0- CC 6.
术语"卤素"为氟、 氯、 溴或碘。 优选为氟、 氯、 溴。 术语"卤代烷基"表示具有一个以上 （包含一个） 卤素取代基的烷基。  The term "halogen" is fluoro, chloro, bromo or iodo. Preferred are fluorine, chlorine, and bromine. The term "haloalkyl" denotes an alkyl group having one or more (including one) halogen substituent.
术语 "卤代烷氧基"表示具有一个以上 （包含一个） 卤素取代基的烷氧基。  The term "haloalkoxy" denotes an alkoxy group having one or more (including one) halogen substituent.
术语"环烷基 "表示全部为碳原子的饱和的单环或多环的环结构。术语" C3-C6环烷基 "是指 具有总共 3至 6个碳原子的饱和的单环或多环环结构。 C3-C6环烷基包括但不限于环丙基、环 丁基、 环戊基、 环己基。 The term "cycloalkyl" denotes a saturated monocyclic or polycyclic ring structure which is all carbon atoms. The term "C 3 -C 6 cycloalkyl" refers to a saturated monocyclic or polycyclic ring structure having a total of from 3 to 6 carbon atoms. C 3 -C 6 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语"环烯基 "是指具有至少一个环碳碳双键的单环或多环烃基取代基。 术语" C3-C6环烯 基"是指 3至 6个碳原子的环烯基。 C3-C6环烯基包括但不限于环戊烯基、 环丁烯基。 术语" C2-C6链烯基 "是指具有一个或多个碳碳双键并具有 2至 6个碳原子的直链或支链烃 基团。 The term "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbyl substituent having at least one cyclic carbon-carbon double bond. The term "C 3 -C 6 cycloalkenyl" refers to a cycloalkenyl group of 3 to 6 carbon atoms. C 3 -C 6 cycloalkenyl includes, but is not limited to, cyclopentenyl, cyclobutenyl. The term "C 2 -C 6 alkenyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms.
术语" C2-C6块基"是指具有一个或多个碳碳三键并具有 2至 6个碳原子的直链或支链烃基 团。 The term "C 2 -C 6 block group" means a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms.
术语" C6-C1Q芳基"表示 6到 10个碳原子的全碳单环或稠合多环基团， 具有完全共轭的 π 电子***。 典型地包括但不限于苯环基、 萘环基。 The term "C 6 -C 1Q aryl" denotes an all-carbon monocyclic or fused polycyclic group of 6 to 10 carbon atoms having a fully conjugated π-electron system. Typically, but not limited to, phenylcyclo, naphthalene ring.
术语"杂芳基 "表示单环或稠合环基团， 含有一个、 两个、 三个或四个选 N、 0或 S的 环杂原子， 其余环原子是 C， 另外具有完全共轭的 π电子***。术语" C2-C1Q杂芳基 "是指在其 环中含有 2至 10个碳原子的杂芳基， 该杂芳基的环原子中还包括一个或多个杂原子。 术语 "C3-C1Q杂芳基 "是指在其环中含有 3至 10个碳原子的杂芳基。 C2-C1Q杂芳基包括但不局限于 1，2，4-***、 呋喃、 噻吩、 咪唑、 噁唑、 噻唑、 吡唑、 嘧啶、 吡啶、 吲哚、 喹啉。 The term "heteroaryl" denotes a monocyclic or fused ring radical containing one, two, three or four ring heteroatoms selected from N, 0 or S, the remaining ring atoms being C and additionally fully conjugated. π electronic system. The term "C 2 -C 1Q heteroaryl" means a heteroaryl group having 2 to 10 carbon atoms in its ring, and the heteroaryl group further includes one or more hetero atoms in the ring atom. The term "C 3 -C 1Q heteroaryl" means a heteroaryl group having from 3 to 10 carbon atoms in its ring. C 2 -C 1Q heteroaryl groups include, but are not limited to, 1,2,4-triazole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, pyridine, hydrazine, quinoline.
术语"杂环烷基"表示含 1个或多个N、 0或 S的杂原子的单环或稠合的饱和环状基团。 术语" C4-C8杂环基 "是指在其环中含有 4至 8个碳原子的杂环基。 C4-C8杂环基包括但不限于 哌嗪子基、 吗啉代基、 哌啶子基、 吡咯烷基等。 The term "heterocycloalkyl" denotes a monocyclic or fused saturated cyclic group containing one or more heteroatoms of N, 0 or S. The term "C 4 -C 8 heterocyclic group" means a heterocyclic group having 4 to 8 carbon atoms in its ring. The C 4 -C 8 heterocyclic group includes, but is not limited to, piperazino, morpholino, piperidino, pyrrolidinyl and the like.
术语 "C6-C1Q桥环基"表示含有 6到 10个碳原子的多环基团， 其中任意两个环共用两个 不直接相连的碳原子。 The term "C 6 -C 1Q bridged ring group" means a polycyclic group having 6 to 10 carbon atoms, wherein any two rings share two carbon atoms which are not directly connected.
某基团为 "共价键"是指该基团两端连接的碳原子或杂原子之间直接相连构成之间无其 他原子的共价键。 本发明还提供上述化合物的制备方法， 但不仅限于下列方法：  A group "covalent bond" means that the carbon atom or hetero atom attached to the two ends of the group is directly connected to form a covalent bond between the other atoms. The present invention also provides a process for the preparation of the above compounds, but is not limited to the following methods:
路线 1  Route 1
Figure imgf000020_0001
Figure imgf000020_0001
Z6、 Z Z Z9的定义同式 (I) 所述。 原料 a与原料 b在碱性条件下发生取代反应， 生成中间体 c， 中间体 c的硝基在保险粉、 锌粉或钯碳的作用下被还原为氨基， 中间体 d的氨基与 3，3-二甲基丁酰氯在氢化钠、 三乙胺 或 N，N-二异丙基乙胺的碱性条件下反应， 得到目标产物。 The definitions of Z 6 and ZZZ 9 are as described in the formula (I). The starting material a and the starting material b are subjected to a substitution reaction under basic conditions to form an intermediate c, and the nitro group of the intermediate c is reduced to an amino group under the action of the insurance powder, zinc powder or palladium carbon, and the amino group of the intermediate d is 3, 3-Dimethylbutyryl chloride is reacted under basic conditions of sodium hydride, triethylamine or N,N-diisopropylethylamine to give the desired product.
Figure imgf000021_0001
Figure imgf000021_0001
( ^ϊ ΪΗ 、 ( ^ϊ Ϊ Η ,
Ε选自^ 、 z4vz3或 ^z z7， Ε环可被 R1和 R2取代， R\ R2、 Z3、 Z Z6、 ZΕ selected from ^, z4 v z3 or ^ z z7 , an anthracene ring may be substituted by R 1 and R 2 , R\ R 2 , Z 3 , ZZ 6 , Z
Z8、 Z9的定义同式 （I) 所述。 The definitions of Z 8 and Z 9 are as defined in the formula (I).
三 (二苯亚甲基丙酮)二钯与 2-二环己基磷 -2'，4'，6'-三异丙基联苯形成配合物， 在碱性条件 下， 催化原料 e发生胺化反应， 得到目标产物。  Tris(diphenylmethyleneacetone)dipalladium forms a complex with 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl, and the alkalization of catalytic starting material e under basic conditions The reaction gives the desired product.
Figure imgf000021_0002
Figure imgf000021_0002
G选自 C3-C1Q杂芳基、 C3-C6环烯基或取代的苯并环烯基， 当 R14为溴、 氯或三氟甲磺酸 基， R15为硼酸基或频那醇硼酸酯基； 当 R14为硼酸基， R15为溴。 G is selected from C 3 -C 1Q heteroaryl, C 3 -C 6 cycloalkenyl or substituted benzocycloalkenyl, when R 14 is bromo, chloro or trifluoromethanesulfonate, R 15 is boric acid or Finacol borate group; when R 14 is a boric acid group, R 15 is bromine.
原料 f与原料 g在氮气保护下， 在碳酸钾的条件下， 通过双三苯基磷二氯化钯的催化发 生 suzuki偶联反应， 得到目标产物。  The raw material f and the raw material g are subjected to suzuki coupling reaction under the protection of nitrogen under the condition of potassium carbonate by bis-triphenylphosphine palladium dichloride to obtain the target product.
路线 4 Route 4
Figure imgf000021_0003
Figure imgf000021_0003
、r  r
E选自^^ 、 ^v^3或 ^z9、z^7， Ε环可被 R1和 R2取代， I 1、 R2、 Z3、 Z Z6、 ZE is selected from ^^ , ^v^ 3 or ^ z9 , z ^ 7 , and the anthracene ring may be substituted by R 1 and R 2 , I 1 , R 2 , Z 3 , ZZ 6 , Z
Z8、 Z9的定义同式 （I) 所述。 The definitions of Z 8 and Z 9 are as defined in the formula (I).
原料 a与原料 h在三乙酰氧基硼氢钠或氰基硼氢化钠的作用下， 发生还原胺化反应， 得 到终产物。
Figure imgf000022_0001
The raw material a and the raw material h are subjected to a reductive amination reaction under the action of sodium triacetoxyborohydride or sodium cyanoborohydride to obtain a final product.
Figure imgf000022_0001
E选自 W z-z ， E环可被 R1和 R2取代， R R2、 Z3、 Z Z6、 Z z\ z9的定义同式 α) 所述。 E is selected from W z- z , the E ring may be substituted by R 1 and R 2 , and the definitions of RR 2 , Z 3 , ZZ 6 , Z z\ z 9 are as defined in the formula α).
原料 a与原料 i在碱性条件下发生取代反应， 得到目标产物。  The starting material a and the starting material i are subjected to a substitution reaction under alkaline conditions to obtain a target product.
式 （I ) 化合物可以使用盐酸***溶液酸化， 直接获得其盐酸盐。 式 （I ) 化合物的盐酸 盐可以通过三乙胺、 饱和碳酸氢钠水溶液或者一定浓度的氢氧化钠水溶液游离出相应的碱。  The compound of the formula (I) can be acidified using a hydrochloric acid diethyl ether solution to directly obtain the hydrochloride salt. The hydrochloride salt of the compound of the formula (I) can be freed from the corresponding base by triethylamine, a saturated aqueous solution of sodium hydrogencarbonate or a certain aqueous solution of sodium hydroxide.
本发明还提供了一种式 (I)化合物或其药学上可接受的盐在制备药物中的用途， 所述药物 用于治疗或预防受 M型钾电流的增强影响的疾病或病症。  The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition which is affected by an enhancement of M-type potassium current.
本发明还提供了一种式 (I)化合物或其药学上可接受的盐在制备药物中的用途， 所述药物 用于预防或治疗治疗对钾通道离子流增加敏感方面， 特别是中枢神经***疾病药物方面的疾 病， 例如受电压门控钾通道的激活影响的疾病或病症。 所述疾病或病症优选地为癫痫、 炎症 性疼痛、 神经性疼痛、 偏头痛、 神经变性疾病、 焦虑障碍、 脑卒中、 ***滥用、 尼古丁戒 断、 酒精戒断或耳鸣。  The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of increased sensitivity to potassium channel ion flux, particularly the central nervous system Diseases in disease drugs, such as diseases or conditions that are affected by activation of voltage-gated potassium channels. The disease or condition is preferably epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, stroke, ***e abuse, nicotine withdrawal, alcohol withdrawal or tinnitus.
本发明还提供了一种式 (I)化合物或其药学上可接受的盐在制备药物中的用途， 所述药物 用于增加哺乳动物特别是人的钾通道中离子流量方面，尤其是提高哺乳动物中 KCNQ2/3通道 的通道开放率方面。  The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing the ion flux in a potassium channel of a mammal, particularly a human, in particular for increasing breastfeeding The channel opening rate of the KCNQ2/3 channel in animals.
本发明还提供了一种药用组合物， 所述组合物包含治疗有效量的式 (I)化合物或其药学上 可接受的盐， 和药学上可接受的载体或稀释剂。  The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
药用组合物的目的是促进化合物对生物体的给药。  The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
治疗有效量， 可以是在某种程度上缓解对象中的疾病或病症的一种或多种症状、 使与疾 病或病症相关或是其病因的一种或多种生理或生物化学参数部分或完全恢复正常、和 /或降低 疾病或病症的发作可能性的量。  A therapeutically effective amount may be one or more symptoms that alleviate one or more symptoms of a disease or condition in a subject, or one or more physiological or biochemical parameters associated with the disease or condition, or a cause thereof. The amount that restores normal, and/or reduces the likelihood of a disease or condition.
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物 活性和性质的赋形剂或稀释剂。  A pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
赋形剂指的是加入到药用组合物中以进一步便利于给予化合物的惰性物质。 赋形剂的实 例包括 （不局限于） 碳酸钙、 磷酸钙、 多种糖类和多种类型的淀粉、 纤维素衍生物、 明胶、 植物油和聚乙二醇。 本文中术语 "钾通道调节剂"指能够引起钾通道电流增加的化合物。 它也指能够增加 KCNQ2/3通道开放率的化合物。 Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Examples of excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. The term "potassium channel modulator" as used herein refers to a compound that is capable of causing an increase in potassium channel current. It also refers to compounds that increase the KCNQ2/3 channel open rate.
术语"药学上可接受的盐"表示保留母体化合物的生物有效性和性质的那些盐， 其具有所 期望的药学活性并且在生物学上和在其它方面的均没有不合要求之处。 这类盐包括：  The term "pharmaceutically acceptable salts" denotes those salts which retain the biological effectiveness and properties of the parent compound, which have the desired pharmaceutical activity and which are not biologically and otherwise undesirable. Such salts include:
(1) 与酸成盐 （酸式盐） ， 通过母体化合物的游离碱与无机酸或有机酸的反应而得； 无 机酸包括但不限于盐酸、 硫酸、 磷酸、 甲磺酸， 有机酸包括但不限于乙酸、 三氯乙酸、 丙酸、 丁酸、 马来酸、 对甲苯磺酸、 苹果酸、 丙二酸、 肉桂酸、 柠檬酸、 富马酸、 樟脑酸、 二葡糖 酸、 天冬氨酸、 酒石酸；  (1) a salt with an acid (acid salt) obtained by the reaction of a free base of a parent compound with an inorganic or organic acid; inorganic acids including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, organic acids including but Not limited to acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic Acid, tartaric acid;
(2) 存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐 (碱式盐） 。  (2) A salt (basic salt) formed by the acid proton present in the parent compound being replaced by a metal ion or by complexation with an organic base.
本发明中所述化合物或其药学上可接受的盐可以通过电生理实验、 铊流实验、 原子吸收 Rb+流出高通量测定实验等方法检测其药理活性。 The compound of the present invention or a pharmaceutically acceptable salt thereof can be tested for pharmacological activity by electrophysiological experiments, turbulence experiments, atomic absorption Rb + efflux high-throughput assays and the like.
膜片钳技术被称为研究离子通道的 "金标准"， 是离子通道功能学研究最重要的技术。 膜 片钳技术运用微玻管电极接触细胞膜， 以千兆欧姆以上的阻抗使之对接， 使与电极尖开口处 相接的细胞膜小片区域 （膜片） 与其周围在电学上分隔， 在此基础上固定电位， 对此膜片上 的离子通道的离子电流进行检测记录。运用膜片钳技术对 KCNQ钾通道调节剂进行功能学验 证。  Patch clamp technology, known as the "gold standard" for studying ion channels, is the most important technique for ion channel functional studies. The patch-clamp technique uses a micro-glass tube electrode to contact the cell membrane and docks it with an impedance of more than a gigaohm, so that the cell membrane area (membrane) that is in contact with the opening of the electrode tip is electrically separated from its surroundings, on the basis of which A fixed potential is used to detect and record the ion current of the ion channel on the diaphragm. Functional verification of KCNQ potassium channel modulators using patch clamp technique.
铊流测定技术作为基于荧光的实验， 在钾离子通道调节剂的高通量筛选中得到广泛的运 用。 铊流检测利用了 KCNQ钾通道对铊离子的通透性， 通过检测铊流入的浓度来测定钾通道 的开放或关闭。 当通道刺激开放以后， 铊离子从细胞外的溶液进入到细胞内， 和细胞内铊敏 感性的染料结合， 通过荧光信号检测铊离子的跨膜流动， 用于筛选钾通道的调节剂。  As a fluorescence-based assay, turbulence assays are widely used in high-throughput screening of potassium channel modulators. The turbulence test utilizes the permeability of the KCNQ potassium channel to the cesium ion, and the opening or closing of the potassium channel is determined by detecting the concentration of the enthalpy inflow. When the channel is stimulated to open, the strontium ions enter the cell from the extracellular solution, bind to the intracellular sensitizing dye, and detect the transmembrane flow of strontium ions by fluorescence signal, which is used to screen the potassium channel regulator.
原子吸收 Rb+流出测定技术在钾离子通道调节剂的高通量筛选中更加快速、 可靠， 并且 具有直接反映离子通道活性及调节剂调节作用的特点。 Rb+与 K+有相近的原子大小， 并且钾 离子通道对于 Rb+具有通透性， 可以通过检测 Rb+流出的浓度来测定钾通道的开放或关闭。 Rb+在 780nm有特异的原子吸收，可以通过原子吸收的方法检测 Rb+浓度。故可以采用原子吸 收光谱测定法通过测定 Rb+流出的高通量测定技术用于筛选钾通道的开放剂或阻断剂。 The atomic absorption Rb + efflux assay is faster and more reliable in high-throughput screening of potassium channel modulators and has a direct reflection of ion channel activity and modulator regulation. Rb + has a similar atomic size to K + , and the potassium ion channel is permeable to Rb + , and the opening or closing of the potassium channel can be determined by detecting the concentration of Rb + efflux. Rb + has a specific atomic absorption at 780 nm, and the Rb + concentration can be detected by atomic absorption. Therefore, an open source or blocker for screening potassium channels can be determined by atomic absorption spectrometry using a high-throughput assay for measuring Rb + efflux.
本发明中所述化合物或其药学上可接受的盐通过电生理实验、 铊流实验、 原子吸收 Rb+ 流出高通量测定实验等方法证实其具有钾离子通道开放的药理活性。 The compound of the present invention or a pharmaceutically acceptable salt thereof is confirmed to have a pharmacological activity of potassium ion channel opening by electrophysiological experiments, turbulence experiments, atomic absorption Rb + efflux high-throughput assays and the like.
具体实施方式 下面通过非限定性实施例来对本发明进行说明， 应当理解为， 此处描述的优选实施例仅 用于说明和解释本发明， 并不用于限定本发明。 detailed description The invention is illustrated by the following non-limiting examples, which are intended to be illustrative and not to be construed as limiting.
实施例一  Embodiment 1
N-(6-(6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -2,4-二甲基吡啶 -3-基) -3,3-二甲基丁酰胺  N-(6-(6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)- 3,3-dimethylbutyramide
Figure imgf000024_0001
Figure imgf000024_0001
6-氯 -2,4-二甲基 -3-硝基吡啶 （化合物 1A)  6-Chloro-2,4-dimethyl-3-nitropyridine (Compound 1A)
2-羟基 -4,6-二甲基 -5-硝基吡啶 （ 820 mg， 4.88 mmol)溶于苯基膦酰二氯 （4.85 mL， 34.2 mmol) ， 反应物在封管中 160 °C反应 8小时， 冷却至室温， 倾入冰水中， 饱和碳酸钠溶液洗 涤， 乙酸乙酯萃取， 旋干有机相溶剂， 使用硅胶柱纯化 （石油醚： 乙酸乙酯 =10: 1 ) 得到化合 物 1A为黄色固体 （760 mg， 79%收率) 。 MS: 187.4 (M+H+).  2-Hydroxy-4,6-dimethyl-5-nitropyridine (820 mg, 4.88 mmol) was dissolved in phenylphosphonic dichloride (4.85 mL, 34.2 mmol), and the reaction was reacted at 160 ° C in a sealed tube. After 8 hours, it was cooled to room temperature, poured into ice water, washed with saturated sodium carbonate solution, extracted with ethyl acetate, and then evaporated to ethyl ether solvent (purified ether (ethyl ether = 10:1) to afford compound 1A as yellow Solid (760 mg, 79% yield). MS: 187.4 (M+H+).
2-(4，6-二甲基 -5-硝基吡啶 -2-基) -6-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉 （化合物 1B) 化合物 lA ( 300 mg， 1.6 mmol)与 6-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉（260 mg， 1.6 mmol) 溶于 20 mL乙醇， 注射器加入二异丙基乙胺 （DIEA，0.53 mL， 3.2 mmol) ， 反应物回流 24 小时， 蒸干溶剂， 所得物使用硅胶柱纯化 （石油醚： 乙酸乙酯 =10: 1 ) 得到化合物 1B为固体 ( 82 mg, 16%收率） 。 MS: 314.6 (M+H+).  2-(4,6-Dimethyl-5-nitropyridin-2-yl)-6-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (Compound 1B Compound 1A (300 mg, 1.6 mmol) and 6-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (260 mg, 1.6 mmol) in 20 mL ethanol, syringe Diisopropylethylamine (DIEA, 0.53 mL, 3.2 mmol) was added, and the mixture was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh (82 mg, 16% yield). MS: 314.6 (M+H+).
6-(6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -2,4-二甲基吡啶 -3-胺 （化合物 1C)  6-(6-Fluoro-3,4-dihydro-1,4-methyleneisoquinoline-2(1H)-yl)-2,4-dimethylpyridine-3-amine (Compound 1C)
化合物 IB ( 82mg， 0.26 mmol)与硫代硫酸钠（0.4 g， 2.1 mmol)溶于 6 mL甲醇及 0.6 mL 水中， 于封管中 90 °C反应 4小时， 反应完成后， 过滤除去固体， 滤液经减压蒸干后， 得到 化合物 1C， 直接用于下一步反应 （74 mg， 100%收率） 。  Compound IB (82 mg, 0.26 mmol) and sodium thiosulfate (0.4 g, 2.1 mmol) were dissolved in 6 mL of methanol and 0.6 mL of water, and reacted at 90 ° C for 4 hours in a sealed tube. After completion of the reaction, the solid was removed by filtration and the filtrate was filtered. After evaporation to dryness under reduced pressure, Compound 1C was obtained, which was applied directly to the next step (74 mg, 100% yield).
N-(6-(6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -2,4-二甲基吡啶 -3-基) -3,3-二甲基丁酰胺 盐酸盐 （化合物 1 )  N-(6-(6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)- 3,3-dimethylbutyramide hydrochloride (Compound 1)
氢化钠 （40 mg， 1.04 mmol)于 0 °C加至化合物 1C ( 74 mg, 0.26 mmol) 的 20 mL四氢 呋喃溶液中，室温搅拌 40分钟后，降温至 0 V ,滴加 3，3-二甲基丁酰氯（0.1 mL, 0.52 mmol) , 该反应物继续室温搅拌 2小时， 反应完成后加入水， 乙酸乙酯萃取， 粗品用制备柱层析色谱 纯化得到 N-(6-(6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -2,4-二甲基吡啶 -3-基) -3,3-二甲基丁 酰胺， 该化合物使用盐酸***溶液酸化后得到化合物 1， 为白色固体 （20 mg， 20%收率） 。  Sodium hydride (40 mg, 1.04 mmol) was added to a solution of compound 1C (74 mg, 0.26 mmol) in 20 mL of THF. Butyryl chloride (0.1 mL, 0.52 mmol), the reaction was stirred at room temperature for 2 hr. After completion of the reaction, water was added, ethyl acetate was evaporated, and the crude product was purified by preparative column chromatography to give N-(6-(6-fluoro- 3,4-Dihydro-1,4-methylene isoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide, The compound was acidified using aq. EtOAc (EtOAc) to afford compound 1 as white solid (20 mg, 20% yield).
MS: 383 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 8.95 (brs, 1H), 7.31 (brs, 1H),7.18 (d, J= 9.6 Hz, 1H), 6.82 (t， J= 9.6 Hz, 1H), 6.36 (brs, 1H)， 5.29 (brs, 1H), 3.72-3.75 (m， 2H), 2.67 (s， 1H) 2.15 (s, 5H)， 2.08-2.11 (m， 1H), 2.03 (s, 3H), 1.89-1.91 (m， 1H), 1.00 (s, 9H). MS: 383 (M+H+).1H NMR (400 MHz, DMSO-6) δ: 8.95 (brs, 1H), 7.31 (brs, 1H), 7.18 (d, J = 9.6 Hz, 1H), 6.82 (t, J= 9.6 Hz, 1H), 6.36 (brs, 1H), 5.29 (brs, 1H), 3.72-3.75 (m, 2H), 2.67 (s, 1H) 2.15 (s, 5H), 2.08-2.11 (m, 1H), 2.03 (s, 3H), 1.89-1.91 (m, 1H), 1.00 (s, 9H).
实施例二  Embodiment 2
N- (2- (4-氯苄 N- (2- (4-氯苄氧基） -4，6-二甲基 -吡啶 -5-基） -3,3-二甲基丁酰胺的制备  Preparation of N-(2-(4-chlorobenzyl N-(2-(4-chlorobenzyloxy)-4,6-dimethyl-pyridin-5-yl)-3,3-dimethylbutanamide
Figure imgf000025_0001
Figure imgf000025_0001
2- (4,6-二甲基 -5-硝基 -2吡啶基） -1，2，3，4-四氢 -1,4-甲氧异喹啉 （化合物 2A)  2-(4,6-Dimethyl-5-nitro-2pyridyl)-1,2,3,4-tetrahydro-1,4-methoxyisoquinoline (Compound 2A)
6-氯 -2,4-二甲基 -3-硝基吡啶 （490mg， 2.63mmol) 和二异丙基乙胺 （ DIE A， 1.9ml， 6-Chloro-2,4-dimethyl-3-nitropyridine (490 mg, 2.63 mmol) and diisopropylethylamine (DIE A, 1.9 ml,
10.52mmol) 加入至 20ml乙腈中， 然后加入化合物 1，2，3，4-四氢 -1,4-亚甲基异喹啉 （400mg，10.52 mmol) was added to 20 ml of acetonitrile, followed by the addition of the compound 1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (400 mg,
2.76mmol),将反应液升温至回流反应 3小时，将乙腈旋干，过柱纯化得到化合物 2A ( 170mg，2.76 mmol), the reaction solution was heated to reflux for 3 hours, acetonitrile was spun and purified by column to afford compound 2A (170 mg,
22%) 。 MS: 296 (M+H+). twenty two%) . MS: 296 (M+H + ).
2- (4,6-二甲基 -5-氨基 -2嘧啶基） -1，2，3，4-四氢 -1,4-甲氧异喹啉 （化合物 2B)  2-(4,6-Dimethyl-5-amino-2pyrimidinyl)-1,2,3,4-tetrahydro-1,4-methoxyisoquinoline (Compound 2B)
本品由化合物 2A和硫代硫酸钠按照化合物 1C的制备方法合成， 72%收率。  This product was synthesized from Compound 2A and sodium thiosulfate according to the preparation method of Compound 1C, 72% yield.
N- (2- (4-氯苄 N- (2- (4-氯苄氧基) -4,6-二甲基 -吡啶 -5-基) -3,3-二甲基丁酰胺 （化合 物 2)  N-(2-(4-chlorobenzyl N-(2-(4-chlorobenzyloxy)-4,6-dimethyl-pyridin-5-yl)-3,3-dimethylbutanamide (compound) 2)
氢化钠 （19.9mg， 0.83 mmol) 于 0 °C加至化合物 2B ( 110 mg， 0.414mmol) 的 20 mL 四氢呋喃溶液中， 室温搅拌 40分钟后， 降温至 0 V , 滴加 3，3-二甲基丁酰氯 （222mg， 1.66 mmol) ， 该反应物继续室温搅拌 2小时， 反应完成后加入水， 乙酸乙酯萃取， 粗品使用石油 醚 /乙酸乙酯 =1 : 1纯化得到化合物 2，为白色固体（40mg，26.4%收率） MS: 364 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.89(d，lH)， 7.33-7.28(m, 2H), 7.08-7.02 (m， 2H),6.37-6.34(s,lH) 5.289-5.286 (d,lH), 3.71-3.34 (m,2H), 2.62-2.60 (m，lH)， 2.14-2.13 (m， 5H)， 2.13-2.01 (m， 1H)， 2.08-2.01(m,3H), 1.87-1.86(m,lH), 1.063(s, 9H). Sodium hydride (19.9 mg, 0.83 mmol) was added to a solution of the compound 2B (110 mg, 0.414 mmol) in 20 mL of THF, and stirred at room temperature for 40 min, then cooled to 0 V, 3,3-dimethyl Base butyryl chloride (222 mg, 1.66 mmol). The reaction was stirred at room temperature for 2 hr. EtOAc was evaporated. (40 mg, 26.4% yield) MS: 364 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.89 (d,lH), 7.33-7.28 (m, 2H), 7.08-7.02 ( m, 2H), 6.37-6.34 (s, lH) 5.289-5.286 (d, lH), 3.71-3.34 (m, 2H), 2.62-2.60 (m, lH), 2.14-2.13 (m, 5H), 2.13 -2.01 (m, 1H), 2.08-2.01 (m, 3H), 1.87-1.86 (m, lH), 1.063 (s, 9H).
实施例  Example
N- (2- ( 3，4-二氢 -1，4-甲氧异喹啉 -2 ( 1H)基） -4，6-二甲基 -5-嘧啶基 -3，3-二甲基叔丁胺的 制备
Figure imgf000025_0002
N-(2-(3,4-dihydro-1,4-methoxyisoquinolin-2(1H)yl)-4,6-dimethyl-5-pyrimidinyl-3,3-dimethyl Preparation of tert-butylamine
Figure imgf000025_0002
2-氯 -4,6-二甲基 -5-硝基嘧啶 （化合物 3A) 本品由 4，6-二甲基 -5-硝基 -2-羟基-嘧啶和二氯苯氧磷按照化合物 1A的制备方法合成， 2 -chloro-4,6-dimethyl-5-nitropyrimidine (Compound 3A) This product is synthesized from 4,6-dimethyl-5-nitro-2-hydroxy-pyrimidine and dichlorophenoxyphosphorus according to the preparation method of compound 1A.
67.7%收率。 MS: 188[M+H]+. 67.7% yield. MS: 188 [M+H] + .
2- (4,6-二甲基 -5-硝基 -2嘧啶基） -1，2，3，4-四氢 -1,4-甲氧异喹啉 （化合物 3B)  2-(4,6-Dimethyl-5-nitro-2pyrimidinyl)-1,2,3,4-tetrahydro-1,4-methoxyisoquinoline (Compound 3B)
本品由化合物 3A和 1，2，3，4-四氢 -1,4-亚甲基异喹啉按照化合物 1B的制备方法合成， 39% 收率。 MS: 297[M+H]+. This product was synthesized from Compound 3A and 1,2,3,4-tetrahydro-1,4-methyleneisoquinoline according to the preparation method of Compound 1B, 39% yield. MS: 297 [M+H] + .
2- (4,6-二甲基 -5-氨基 -2嘧啶基） -1，2，3，4-四氢 -1,4-甲氧异喹啉 （化合物 3C)  2-(4,6-Dimethyl-5-amino-2pyrimidinyl)-1,2,3,4-tetrahydro-1,4-methoxyisoquinoline (Compound 3C)
本品由化合物 3B和硫代硫酸钠按照化合物 1C的制备方法合成， 86%收率。  This product was synthesized from Compound 3B and sodium thiosulfate according to the preparation method of Compound 1C, 86% yield.
N- (2- (3,4-二氢 -1,4-甲氧异喹啉 -2 ( 1H)基） -4,6-二甲基 -5-嘧啶基 -3,3-二甲基叔丁胺（化 合物 3 )  N-(2-(3,4-dihydro-1,4-methoxyisoquinolin-2(1H)yl)-4,6-dimethyl-5-pyrimidinyl-3,3-dimethyl Tert-butylamine (compound 3)
本品由氢化钠和化合物 3C按照化合物 2的制备方法合成， 46.1%收率。 NMR (400 MHz, DMSO-d6) δ: 9.07(d, 1Η), 7.35 -7.33(m, 1H), 7.25-7.30 (m， 1H), 7.12-7.08 (m， 1H), 7.06-7.04 (m， 1H), 5.42 (s, 1H), 3.74-3.69 (m， 2H), 2.82-2.80 (m， 1H), 2.35-2.32 (m， 5H)， 2.08-2.01 (m，  This product was synthesized from sodium hydride and compound 3C according to the preparation method of compound 2, 46.1% yield. NMR (400 MHz, DMSO-d6) δ: 9.07 (d, 1 Η), 7.35 -7.33 (m, 1H), 7.25-7.30 (m, 1H), 7.12-7.08 (m, 1H), 7.06-7.04 (m , 1H), 5.42 (s, 1H), 3.74-3.69 (m, 2H), 2.82-2.80 (m, 1H), 2.35-2.32 (m, 5H), 2.08-2.01 (m,
4H)，1.88-1.86(m， 2H) 1.06 (s, 9H). 4H), 1.88-1.86 (m, 2H) 1.06 (s, 9H).
实施例四  Embodiment 4
N-(2-((lS，4R)-6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -4,6-二甲基嘧啶 -5-基) -3,3-二甲 基丁酰胺的制备
Figure imgf000026_0001
N-(2-((lS,4R)-6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine -5-yl) Preparation of -3,3-dimethylbutanamide
Figure imgf000026_0001
(lS，4R)-2-(4，6-二甲基 -5-硝基嘧啶 -2-基) -6-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉（化合物 4A) 本品由 ( IS, 4R) -6-氟 -1， 2， 3， 4-四氢 -1， 4-甲基异喹啉 （200 mg， 1.33 mmol) 和 2- 氯 -4， 6-二甲基 -5-硝基嘧啶按照化合物 1B的制备方法合成， 60% 收率。  (lS,4R)-2-(4,6-Dimethyl-5-nitropyrimidin-2-yl)-6-fluoro-1,2,3,4-tetrahydro-1,4-methylene Isoquinoline (Compound 4A) This product consists of ( IS, 4R) -6-fluoro-1, 2, 3, 4-tetrahydro-1, 4-methylisoquinoline (200 mg, 1.33 mmol) and 2- Chloro-4,6-dimethyl-5-nitropyrimidine was synthesized according to the preparation method of Compound 1B in 60% yield.
2-((lS，4R)-6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -4,6-二甲基嘧啶 -5-胺 （化合物 4B) 本品由化合物 4A和硫代硫酸钠按照化合物 1C的制备方法合成， 直接用于下一步反应。 N-(2-((lS，4R)-6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -4,6-二甲基嘧啶 -5-基) -3,3-二甲 基丁酰胺 （化合物 4)  2-((lS,4R)-6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine-5- Amine (Compound 4B) This product was synthesized from Compound 4A and sodium thiosulfate according to the preparation method of Compound 1C, and was used directly for the next reaction. N-(2-((lS,4R)-6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine -5-yl)-3,3-dimethylbutanamide (compound 4)
本品由 3，3-二甲基丁酰氯和化合物 4B按照化合物 2的制备方法合成， 70%收率。 MS: 363.7 (M+H+). 1H NMR (400 MHz, DMSO) δ: 7.25 (t， J= 7.6 Hz, 1H)， 7.00 (d， J= 10.4 Hz, 1H)， 6.73 (t， J= 8 Hz, 1H), 6.51 (s, 1H), 5.53 (s, 1H), 3.80 (d, J= 9.6 Hz, 1H), 3.7 (s, 1H), 2.98 (d, J= 10 Hz, 1H), 2.23 (s， 8H)， 2.14-1.96 (m， 2H), 1.12 (s， 9H). 实施例五 This product is synthesized from 3,3-dimethylbutyryl chloride and compound 4B according to the preparation method of compound 2, 70% yield. MS: 363.7 (M+H+). 1H NMR (400 MHz, DMSO) δ: 7.25 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 10.4 Hz, 1H), 6.73 (t, J= 8 Hz, 1H), 6.51 (s, 1H), 5.53 (s, 1H), 3.80 (d, J= 9.6 Hz, 1H), 3.7 (s, 1H), 2.98 (d, J= 10 Hz, 1H), 2.23 (s, 8H), 2.14-1.96 (m, 2H), 1.12 (s, 9H). Embodiment 5
N-(4-(3， -二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺的制备  N-(4-(3,-Dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethyl Preparation of butanamide
Figure imgf000027_0001
Figure imgf000027_0001
3-羰基 -2,3-二氢 -1H-茚小甲酸 （化合物 5A)  3-carbonyl-2,3-dihydro-1H-indole small formic acid (Compound 5A)
苯基丁二酸酐（10g， 57mmol)溶于 1，2-二氯乙烷（200 mL)后， 于 0 °C滴加至三氯化 铝 （17 g， 130mmol) 的 1， 2-二氯乙烷 （50mL) 溶液中， 滴加完毕后在室温继续搅拌 1小 时， 之后在 0 °C加入水 （50 mL) 淬灭， 乙酸乙酯萃取 （3X60mL) ， 有机相减压蒸干得到 化合物 5A， 为浅黄色油状产物 （8.3 g， 83%收率） 。  Phenyl succinic anhydride (10 g, 57 mmol) was dissolved in 1,2-dichloroethane (200 mL) and added dropwise to aluminum trichloride (17 g, 130 mmol) of 1,2-dichloromethane at 0 °C. In the solution of hexane (50 mL), the mixture was stirred at room temperature for 1 hour, then added with water (50 mL) at 0 ° C, and ethyl acetate (3×60 mL). , product as light yellow oil (8.3 g, 83% yield).
3-幾基 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 5B)  3-mono- 2,3-dihydro-1H-indole methyl formate (compound 5B)
化合物 5A (8.3g， 47.2 mmol) 溶于 200 mL甲醇后， 滴加 5 mL浓硫酸， 反应液加热回 流 5小时， 旋干溶剂， 所得混合物使用石油醚： 乙酸乙酯 =10:1纯化得到化合物 5B为淡黄色 油状产物 （6.7 g， 76%收率） 。  After compound 5A (8.3 g, 47.2 mmol) was dissolved in 200 mL of methanol, 5 mL of concentrated sulfuric acid was added dropwise, and the reaction mixture was heated under reflux for 5 hours, and the solvent was evaporated to dryness. The mixture was purified using petroleum ether: ethyl acetate = 10:1 5B was a pale yellow oily product (6.7 g, 76% yield).
3-肟 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 5C)  3-肟 -2,3-dihydro -1H-indole methyl formate (compound 5C)
盐酸羟胺 （3.71 g， 53.4 mmol) 和乙酸钠 （5.84g， 71.2 mmol) 溶于 25mL水中， 化 合物 5B (6.7 g， 35.6 mmol) 及乙醇 （95%， 150 mL) 缓慢滴加到上述溶液中， 该反应液加 热回流 3小时， 旋干溶剂， 加入水， 乙酸乙酯（3X50mL)萃取， 有机相用无水硫酸钠干燥， 减压旋干溶剂得到化合物 5C为白色固体 （5.7 g， 79%收率） 。  Hydroxylamine hydrochloride (3.71 g, 53.4 mmol) and sodium acetate (5.84 g, 71.2 mmol) were dissolved in 25 mL of water, and compound 5B (6.7 g, 35.6 mmol) and ethanol (95%, 150 mL) were slowly added dropwise to the above solution. The reaction mixture was heated to reflux for 3 hrs, EtOAc (EtOAc m. Rate).
3-氨基 -2,3-二氢 -1H-茚小甲酸甲酯的盐酸盐 （化合物 5D)  Hydrochloride of 3-amino-2,3-dihydro-1H-indole methyl formate (Compound 5D)
化合物 5C (5.7 g， 27.9 mmol)溶于 250 mL甲醇后， 加入 6 mL浓盐酸及 0.6 g 10%的靶 碳催化剂， 在 40psi下氢化还原 48h。 过滤除去催化剂， 将滤液减压旋干得到白色固体， 该 粗产物使用乙醇 /甲基叔丁基醚重结晶得到化合物 5D为白色固体 （5g， 75%收率） 。  After compound 5C (5.7 g, 27.9 mmol) was dissolved in 250 mL of methanol, 6 mL of concentrated hydrochloric acid and 0.6 g of a 10% target carbon catalyst were added and hydrogenated at 40 psi for 48 h. The catalyst was removed by filtration, and the filtrate was evaporated to dryness crystals crystals crystals crystals crystals
3-氨基 -2,3-二氢 -1H-茚小甲酸的盐酸盐 （化合物 5E)  Hydrochloride of 3-amino-2,3-dihydro-1H-indole small formic acid (Compound 5E)
化合物 5D (5 g， 20.7 mmol)溶于 10 mL水后， 加入 10 mL 4N浓盐酸后， 加热回流 5 h， 使用减压蒸馏旋干溶剂后， 得到目标化合物的盐酸盐粗产品， 该粗产物使用乙醇 /甲基叔丁基 醚重结晶得到化合物 5E为白色固体 （4g， 86%收率） 。  After compound 5D (5 g, 20.7 mmol) was dissolved in 10 mL of water, 10 mL of 4N concentrated hydrochloric acid was added, and the mixture was heated to reflux for 5 h, and the solvent was evaporated to dryness to give the crude salt of the title compound as a crude compound. The product was recrystallized from ethanol / methyl tert-butyl ether to afford compound 5E as a white solid (4 g, 86% yield).
1，2-二氢 -1,4-亚甲基异喹啉 -3(4氢) -酮 （化合物 5F) 化合物 5E (2g， 9.4 mmol) 及吡啶 （2.3 mL， 28.2 mmol) 溶于 lOOmL乙腈中， 加入二 环己基碳二亚胺 （DCC，2.1 g， 10.3 mmol) 的乙腈 （20mL) 溶液。 反应液加热回流 1 h， 不 溶物 （二环己基脲） 使用滤纸过滤除去， 滤液减压旋干得到化合物 5F (1.5 g， 100%收率） 。 该化合物不经纯化， 直接用于下步反应。 1,2-dihydro-1,4-methylene isoquinoline-3(4-hydro)-one (compound 5F) Compound 5E (2 g, 9.4 mmol) and pyridine (2.3 mL, 28.2 mmol) were dissolved in EtOAc EtOAc EtOAc (EtOAc) The reaction solution was heated to reflux for 1 h, and the insoluble material (dicyclohexylurea) was removed by filtration using a filter paper, and the filtrate was evaporated to dryness to give compound 5F (1.5 g, 100% yield). This compound was used in the next step without purification.
1，2，3，4-四氢 -1,4-亚甲基异喹啉 （化合物 5G)  1,2,3,4-tetrahydro-1,4-methylene isoquinoline (compound 5G)
四氢铝锂 （0.78 g， 20.6mmol) 溶于 50 mL四氢呋喃中， 冰水浴降温至 0 °C后， 滴加化 合物 5F (1.5 g, 9.4 mmol) 的四氢呋喃 （10mL) 溶液， 滴加过程中保持反应液的内温不超 过 10 V。滴加完毕后， 反应液回流 3 h。 降至室温后， 过量的四氢铝锂使用 Fieser方法除去。 过滤除去铝盐， 滤液使用乙酸乙酯萃取 （3X50mL) ， 有机相减压旋干得到化合物 5G为黄 色油状， 该产物不经纯化直接用于下一步反应中。  Lithium tetrahydrogen aluminum (0.78 g, 20.6 mmol) was dissolved in 50 mL of tetrahydrofuran. After cooling to 0 °C in ice-water bath, a solution of compound 5F (1.5 g, 9.4 mmol) in tetrahydrofuran (10 mL) was added dropwise during the dropwise addition. The internal temperature of the reaction solution does not exceed 10 V. After the addition was completed, the reaction solution was refluxed for 3 h. After dropping to room temperature, excess lithium aluminum hydride was removed using the Fieser method. The aluminum salt was removed by filtration, and the filtrate was applied to ethyl acetate (3.times.50mL), and the organic phase was evaporated to dryness to afford compound 5 g as yellow oil.
N-(4-(3，4-二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 N-(4-(3,4-Dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethyl Butylamide
5) 5)
三 (二苯亚甲基丙酮)二钯 （Pd2(dba)3， 73 mg, 0.103 mmol) 禾 B 2-二环己基磷 -2'，4'，6'-三异 丙基联苯 （X-phos， 98 mg, 0.206 mmol) 溶于 25 mL甲苯中搅拌 15 min， 之后加入化合物 5G (150mg， 1.03 mmol)， N- (4-溴代 -2,6-二甲基苯基) -3-甲基丁酰胺 (337 mg, 1.13 mmol) 及 t-BuOK (叔丁醇钾， 0.23 g， 2.06 mmol) 。 该反应液于 110°C封管反应 8 h， 之后减压旋干 溶剂， 石油醚： 乙酸乙酯 =5:1纯化， 纯化后产物在甲醇 /乙酸乙酯 /石油醚中重结晶得到化合物 5为白色固体（250 mg, 67%收率）。 MS: 363 (M+H+).1H NMR (400 MHz, CDC13) δ: 8.74 (s, 1H), 7.30-7.35 (m, 2H)， 7.03-7.07 (m, 2H)， 6.37 (s, 2H), 5.07 (s, 1H), 3.85 (dd, J= 3.2, J= 8 Hz, 1H), 3.68 (s， 1H), 2.46 (d,J= 7.6 Hz, 1H), 2.24 (s， 1H), 2.14-2.19 (m， 7H), 1.86 (d,J= 7.2 Hz, 1H): 1.160， 9H)， 1.00 (s, 1H). Tris(diphenylmethyleneacetone)dipalladium (Pd 2 (dba) 3 , 73 mg, 0.103 mmol) and B 2 -dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl ( X-phos, 98 mg, 0.206 mmol) was dissolved in 25 mL of toluene for 15 min then added compound 5G (150 mg, 1.03 mmol), N- (4-bromo-2,6-dimethylphenyl) 3-methylbutyramide (337 mg, 1.13 mmol) and t-BuOK (potassium tert-butoxide, 0.23 g, 2.06 mmol). The reaction solution was sealed at 110 ° C for 8 h, then the solvent was evaporated to dryness under reduced pressure, ethyl ether: ethyl acetate = 5:1, and the purified product was recrystallized from methanol / ethyl acetate / petroleum ether to give compound 5 It was a white solid (250 mg, 67% yield). MS: 363 (M+H+).1H NMR (400 MHz, CDC1 3 ) δ: 8.74 (s, 1H), 7.30-7.35 (m, 2H), 7.03-7.07 (m, 2H), 6.37 (s, 2H ), 5.07 (s, 1H), 3.85 (dd, J= 3.2, J= 8 Hz, 1H), 3.68 (s, 1H), 2.46 (d, J= 7.6 Hz, 1H), 2.24 (s, 1H) , 2.14-2.19 (m, 7H), 1.86 (d, J = 7.2 Hz, 1H) : 1.160, 9H), 1.00 (s, 1H).
实施例六  Embodiment 6
N-(4-((lS，4R)-6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基丁 酰胺的制备 N-(4-((lS,4R)-6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethyl Preparation of phenyl)-3,3-dimethylbutanamide
Figure imgf000029_0001
Figure imgf000029_0001
2- ( 3-氟苯基） 乙酸乙酯 （化合物 6A)  2-( 3-fluorophenyl)acetate (Compound 6A)
本品由 3-氟苯乙酸和乙醇按照化合物 5B的制备方法合成， 97% 收率。  This product is synthesized from 3-fluorophenylacetic acid and ethanol according to the preparation method of compound 5B, 97% yield.
2—二甲基- ( 3-氟苯基） 丁二酸 （化合物 6B)  2-dimethyl-(3-fluorophenyl)succinic acid (compound 6B)
化合物 6A ( 70 g, 0.28 mol) 溶于干燥的四氢呋喃 （1.5 L) 后， 冷却至 -78 °C， 滴加六甲 基二硅基胺基钠 C2 M，211 mL，0.42 mol)， 并保持温度稳定在 -78 搅拌一个小时， 然后加入 溴乙酸乙酯 （320.8 g， 1.92 mol) 。 该反应液在 -78 搅拌一个小时， 然后再在 -40 °C搅拌 两个小时。 反应结束后， 加入 70 ml醋酸的***溶液， 过滤， 滤液旋干， 柱色谱分离， 用石 油醚： 乙酸乙酯 =3: 1纯化得到化合物 6B为淡黄色油状产物 （78 g， 98% 收率） 。  Compound 6A (70 g, 0.28 mol) was dissolved in dry tetrahydrofuran (1.5 L), cooled to -78 ° C, hexamethyldisilazide sodium C2 M, 211 mL, 0.42 mol The temperature was stabilized at -78 for one hour, then ethyl bromoacetate (320.8 g, 1.92 mol) was added. The reaction was stirred at -78 for one hour and then at -40 °C for two hours. After the reaction, 70 ml of a solution of acetic acid in diethyl ether was added, and the filtrate was evaporated to dryness. ).
2- ( 3-氟苯基） 丁二酸 （化合物 6C )  2-( 3-fluorophenyl) succinic acid (compound 6C)
化合物 6B ( 75 g， 280 mmol) 溶于水 （1 L) ， 加入氢氧化钾 （136 g， 2.8 mmol) 后 回流 20个小时。 冷却至室温， 用稀盐酸 （1 M) 中和至 PH=6后有大量沉淀析出， 过滤得到 粗产物， 真空干燥后得到化合物 6C为白色固体 （45 g， 87% 收率） 。  Compound 6B (75 g, 280 mmol) was dissolved in water (1 L). After cooling to room temperature, a large amount of precipitate was precipitated from dilute hydrochloric acid (1 M) to pH = 6 and filtered to give a crude product which was obtained as a white solid (45 g, 87% yield).
3- ( 3-氟苯基） 丁二酸酐 （化合物 6D)  3-( 3-fluorophenyl) succinic anhydride (compound 6D)
将化合物 6C ( 75 g， 0.354 mol) ， 乙酰氯 （500 mL)和氯化亚砜（500 mL) 的混合物加 热回流三个小时。 将溶剂旋干后得到化合物 6D的粗产物， 该化合物不经纯化， 直接用于下 步反应。  A mixture of compound 6C (75 g, 0.354 mol), acetyl chloride (500 mL) and thionyl chloride (500 mL) was refluxed for three hours. The solvent was spun dry to give the crude product of compound 6D, which was used in the next step without purification.
6-氟 -3-氧代 -2,3-二氢 -1氢-茚 -1-甲酸 （化合物 6E)  6-Fluoro-3-oxo-2,3-dihydro-1hydrogen-purine-1-carboxylic acid (Compound 6E)
本品由化合物 6D的粗产物和三氯化铝按照化合物 5A的制备方法合成， 收率 73%。  This product was synthesized from the crude product of Compound 6D and aluminum trichloride according to the preparation method of Compound 5A, yield 73%.
6-氟 -3-氧代 -2,3-二氢 -1氢-茚 -1-甲酸甲酯 （化合物 6F)  6-Fluoro-3-oxo-2,3-dihydro-l-hydrogen-indole-1-methylcarboxylate (Compound 6F)
本品由化合物 6E和甲醇按照化合物 5B的制备方法合成， 76%收率。  This product was synthesized from Compound 6E and methanol according to the preparation method of Compound 5B, 76% yield.
6-氟 -3-肟 -2,3-二氢 -1氢-茚小甲酸甲酯 （化合物 6G)  6-Fluoro-3-indole-2,3-dihydro-1hydrogen-hydrazide methyl formate (compound 6G)
本品由盐酸羟胺和化合物 6F按照化合物 5C的制备方法合成， 92%收率。  This product was synthesized from hydroxylamine hydrochloride and compound 6F according to the preparation method of compound 5C, 92% yield.
6-氟 -3-氨基 -2,3-二氢 -1氢-茚 -1-甲酸甲酯的盐酸盐 （化合物 6H) 本品由化合物 6G和浓盐酸按照化合物 5D的制备方法合成，还原氢化条件为 60psi， 75% 收率。 Hydrochloride of 6-fluoro-3-amino-2,3-dihydro-1hydro-indole-1-carboxylate (compound 6H) This product is synthesized from the compound 6G and concentrated hydrochloric acid according to the preparation method of the compound 5D, and the reduction hydrogenation condition is 60 psi, 75% yield.
6-氟 -3-氨基 -2,3-二氢 -1氢-茚 -1-甲酸的盐酸盐 （化合物 61)  6-Fluoro-3-amino-2,3-dihydro-1hydrogen-indole-1-carboxylic acid hydrochloride (Compound 61)
本品由化合物 6H按照化合物 5E的制备方法合成， 87%收率。  This product was synthesized from Compound 6H according to the preparation method of Compound 5E, with a yield of 87%.
(lS，4R)-6-氟 -1,2-二氢 -1,4-亚甲基 -3(4氢) -酮 （化合物 6J)  (lS,4R)-6-fluoro-1,2-dihydro-1,4-methylene-3(4H)-one (Compound 6J)
本品由化合物 61和二环己基碳二亚胺按照化合物 5F的制备方法合成， 77%收率。 该化 合物不经纯化， 直接用于下步反应。  This product was synthesized from Compound 61 and dicyclohexylcarbodiimide according to the preparation method of Compound 5F in 77% yield. This compound was used in the next step without purification.
(lS，4R)-6-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉 （化合物 6K)  (lS,4R)-6-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (compound 6K)
本品由化合物 6J按照化合物 5G的制备方法合成， 该产物不经纯化直接用于下一步反应 中。  This product was synthesized from the compound 6J according to the preparation method of the compound 5G, and the product was used in the next reaction without purification.
N-(4-((lS，4R)-6-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基丁 酰胺 （化合物 6)  N-(4-((lS,4R)-6-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethyl Phenyl) -3,3-dimethylbutanamide (compound 6)
本品由化合物 6K和 N- (4-溴代 -2,6-二甲基苯基） -3-甲基丁酰胺及叔丁醇钾按照化合物 5的制备方法合成， 43%收率。 MS: 381 (M+H+). 1H NMR (400 MHz, DMSO) δ: 7.21 (t，J= 3 Hz, 1H), 7.01 (d, J= 1.6 Hz, 1H), 6.99 (t, J= 3 Hz, 2H), 6.44 (s, 1H), 6.36 (s, 2H), 4.94 (s, 1H), 3.84-3.81 (m， 1H), 3.67 (s， 1H), 2.45 (d, J= 8.4 Hz, 1H), 2.25 (s， 2H), 2.20 (s， 7H), 2.08 (d， J= 8.8 Hz, 1H), 1.14 (s， 9H)， 1.00 (s， 1H). This product was synthesized from the compound 6K and N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide and potassium t-butoxide according to the preparation method of compound 5, 43% yield. MS: 381 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 7.21. (t, J = 3 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.99 (t, J = 3 Hz, 2H), 6.44 (s, 1H), 6.36 (s, 2H), 4.94 (s, 1H), 3.84-3.81 (m, 1H), 3.67 (s, 1H), 2.45 (d, J= 8.4 Hz, 1H), 2.25 (s, 2H), 2.20 (s, 7H), 2.08 (d, J= 8.8 Hz, 1H), 1.14 (s, 9H), 1.00 (s, 1H).
实施例七  Example 7
N-(4-(5-氟 -3，4-二氢 -1，4-甲螺基 -2(1H)-基) -2，6-二甲苯基) -3，3-二甲基丁酰胺盐酸盐的制备  N-(4-(5-fluoro-3,4-dihydro-1,4-methylspiro-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Preparation of amide hydrochloride
Figure imgf000030_0001
Figure imgf000030_0001
2-氟苯乙酸乙酯 （化合物 7A)  Ethyl 2-fluorophenyl (Compound 7A)
本品由 2-氟苯乙酸和乙醇按照化合物 5B的制备方法合成， 95%收率。  This product is synthesized from 2-fluorophenylacetic acid and ethanol according to the preparation method of compound 5B, 95% yield.
2-氟 -2-苯丁二酸二乙酯 （化合物 7B)  Diethyl 2-fluoro-2-phenylsuccinate (Compound 7B)
本品由化合物 7A和 2-溴乙酸乙酯按照化合物 6B的制备方法合成， 79%收率。  This product was synthesized from Compound 7A and 2-bromoacetic acid ethyl ester according to the preparation of Compound 6B, with a yield of 79%.
2-氟 -2-苯丁二酸 （化合物 7C)  2-fluoro-2-benzenesuccinic acid (compound 7C)
本品由化合物 7B和氢氧化钾按照化合物 6C的制备方法合成， 81%的收率。 2—氟 -2-苯环丁二酸酐 （化合物 7D) This product was synthesized from Compound 7B and potassium hydroxide according to the preparation method of Compound 6C in a yield of 81%. 2-fluoro-2-phenylcyclosuccinic anhydride (compound 7D)
本品由 2-氟 -2-苯丁二酸、 乙酰氯和二氯亚砜按照化合物 6D的制备方法合成， 粗品直接 投下步反应。  This product is synthesized from 2-fluoro-2-benzenesuccinic acid, acetyl chloride and thionyl chloride according to the preparation method of compound 6D, and the crude product is directly subjected to a step reaction.
7-氟 -3-羰基 -2,3-二氢 -1H-茚 -1-甲酸 （化合物 7E)  7-Fluoro-3-carbonyl-2,3-dihydro-1H-indole-1-carboxylic acid (Compound 7E)
本品由化合物 7D和三氯化铝按照化合物 5A的制备方法合成， 41%收率。  This product was synthesized from Compound 7D and aluminum trichloride according to the preparation method of Compound 5A, 41% yield.
甲基 7-氟 3-羰基 -2,3-二氢 H-茚 1-甲酸甲酯 （化合物 7F)  Methyl 7-fluoro 3-carbonyl -2,3-dihydro H-indole 1-methylcarboxylate (Compound 7F)
本品由化合物 7E和甲醇按照化合物 5B的制备方法合成， 99%收率。  This product was synthesized from the compound 7E and methanol according to the preparation method of the compound 5B in a yield of 99%.
甲基 7-氟 -3- (羟胺 )-2，3-二氢 -1H-茚小甲酸甲酯 （化合物 7G)  Methyl 7-fluoro-3-(hydroxylamine)-2,3-dihydro-1H-indole methyl formate (compound 7G)
本品由盐酸羟胺和化合物 7F按照化合物 5C的制备方法合成， 该产物直接用于下一步反 应。  This product is synthesized from hydroxylamine hydrochloride and compound 7F according to the preparation method of compound 5C, and the product is directly used for the next reaction.
3-氨基 -7-氟 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 7H)  3-amino-7-fluoro-2,3-dihydro-1H-indole methyl formate (compound 7H)
化合物 7G ( 550 mg， 2.5 mmol)溶于 10 mL甲醇后， 加入 2.5 mL的 4M盐酸及 0.65 g锌 粉， 然后在 50°C下搅拌半小时， 过滤， 滤液用氢氧化钠调至 pH=8， 乙酸乙酯萃取分离， 干 燥后浓縮得到化合物 7H粗品 500mg， 为黄色油状物。 直接用于下一步反应， 没有进一步纯 化。  After compound 7G (550 mg, 2.5 mmol) was dissolved in 10 mL of methanol, 2.5 mL of 4M hydrochloric acid and 0.65 g of zinc powder were added, and then stirred at 50 ° C for half an hour, filtered, and the filtrate was adjusted to pH = 8 with sodium hydroxide. The residue was extracted with ethyl acetate. Used directly in the next reaction without further purification.
3-氨基 -7-氟 -2,3-二氢 -1H-茚 -1-甲酸 （化合物 71)  3-amino-7-fluoro-2,3-dihydro-1H-indole-1-carboxylic acid (Compound 71)
本品由化合物 7H和氢氧化钾按照化合物 6C的制备方法合成， 该产物直接用于下一步， 没有进一步纯化。  This product was synthesized from Compound 7H and potassium hydroxide according to the preparation of Compound 6C. This product was used directly in the next step without further purification.
5-氟 -1,2-二氢 -1,4-甲螺基异喹啉 -3(4H)-酮 （化合物 7J)  5-fluoro-1,2-dihydro-1,4-methylspiroisoquinoline-3(4H)-one (Compound 7J)
本品由化合物 71和二环己基碳二亚胺按照化合物 5F的制备方法合成， 该产物不经纯化 直接用于下一步反应。  This product was synthesized from Compound 71 and dicyclohexylcarbodiimide according to the preparation method of Compound 5F. This product was used for the next reaction without purification.
5-氟 -1，2，3，4-四氢 -1,4-甲螺基异喹啉 （化合物 7K)  5-fluoro-1,2,3,4-tetrahydro-1,4-methylspiroisoquinoline (compound 7K)
本品由化合物 7J按照化合物 5G的制备方法合成，该产物不经纯化直接用于下一步反应。  This product was synthesized from the compound 7J according to the preparation method of the compound 5G, and the product was used for the next reaction without purification.
N-(4-(5-氟 -3,4-二氢 -1,4-甲螺基 -2(1H)-基) -2,6-二甲苯基) -3,3-二甲基丁酰胺盐酸盐 （化合 物 7)  N-(4-(5-fluoro-3,4-dihydro-1,4-methylspiro-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide hydrochloride (compound 7)
Pd2(dba)3 ( 55 mg， 0.05 mmol) 禾 B X-phos (24 mg, 0.05 mmol) 溶于 25 mL叔丁醇中搅拌 15 min, 之后加入化合物 7K ( 196 mg， 1.2 mmol) ， N- (4-溴代 -2,6-二甲基苯基） -3,3-二甲基 丁酰胺 （297 mg， 1.0 mmol) 及叔丁醇钾 （448 mg， 4.0 mmol) 。 该反应液于 120°C反应 16 h， 之后减压旋干溶剂， 剩余物通过硅胶柱色谱分离纯化， 然后再用氯化氢***溶液酸化得到化 合物 7为黄色固体（20 mg, 5%收率）， 5%收率。 MS: 381 (M+H+).1H NMR (400 MHz, DMSO) δ: 8.73 (s, 1H), 7.18-7.20(m, 1H)， 7.06-7.08 (m, 1H)， 6.89 (t, J= 8.8 Hz, 1H), 6.37 (s, 2H), 5.13 (s 1H), 3.89 (s， 1H), 3.76-3.78 (m， 1H), 2.27 (d, J= 7.6 Hz, 1H), 2.10 (s， 3H), 2.99 (s， 5H) 1.88 (m， 1H), 1.00 (s, 9H). Pd 2 (dba) 3 ( 55 mg, 0.05 mmol) and B X-phos (24 mg, 0.05 mmol) dissolved in 25 mL of tert-butanol for 15 min, then added compound 7K (196 mg, 1.2 mmol), N - (4-Bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (297 mg, 1.0 mmol) and potassium tert-butoxide (448 mg, 4.0 mmol). The reaction mixture was reacted at 120 ° C for 16 h, then the solvent was evaporated to dryness. 5% yield. MS: 381 (M+H + ).1H NMR (400 MHz, DMSO) δ: 8.73 (s, 1H), 7.18-7.20 (m, 1H), 7.06-7.08 (m, 1H), 6.89 (t, J= 8.8 Hz, 1H), 6.37 (s, 2H), 5.13 (s 1H ), 3.89 (s, 1H), 3.76-3.78 (m, 1H), 2.27 (d, J= 7.6 Hz, 1H), 2.10 (s, 3H), 2.99 (s, 5H) 1.88 (m, 1H), 1.00 (s, 9H).
实施例八  Example eight
N-(4-(8-氟 -3，4-二氢 -1，4-亚甲基异喹啉 -2(1-氢) -yl)-2，6-二甲基苯基) -3，3-二甲基丁酰胺的 制备  N-(4-(8-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1-hydro)-yl)-2,6-dimethylphenyl)-3 , 3-dimethylbutyramide preparation
Figure imgf000032_0001
Figure imgf000032_0001
2- (2-氯 -5-氟苯基） 乙酸乙酯 （化合物 8A)  2-(2-Chloro-5-fluorophenyl)acetate (Compound 8A)
本品由 2-氯 -5-氟苯乙酸和乙醇按照化合物 5B的制备方法合成， 99% 收率。  This product is synthesized from 2-chloro-5-fluorophenylacetic acid and ethanol according to the preparation method of compound 5B, yield 99%.
2-二甲基- (2-氯 -5-氟苯基） 丁二酸二乙酯 （化合物 8B)  2-Dimethyl-(2-chloro-5-fluorophenyl) diethyl succinate (Compound 8B)
本品由化合物 8A和溴乙酸乙酯按照化合物 6B的制备方法合成， 97% 收率。  This product was synthesized from Compound 8A and ethyl bromoacetate according to the preparation method of Compound 6B, yield 97%.
2- (2-氯 -5-氟苯基） 丁二酸 （化合物 8C)  2-(2-Chloro-5-fluorophenyl) succinic acid (Compound 8C)
本品由化合物 8B按照化合物 6C的制备方法合成， 93% 收率。  This product was synthesized from Compound 8B according to the preparation method of Compound 6C, yield 93%.
3- (2-氯 -5-氟苯基） 丁二酸酐 （化合物 8D)  3-(2-Chloro-5-fluorophenyl) succinic anhydride (Compound 8D)
本品由化合物 8C按照化合物 6D的制备方法合成， 该产物不经纯化， 直接用于下一步反 应。  This product was synthesized from the compound 8C according to the preparation method of the compound 6D, and the product was directly used for the next reaction without purification.
4-氟 -7-氯 -3-氧代 -2,3-二氢 -1H-茚 -1-甲酸 （化合物 8E)  4-fluoro-7-chloro-3-oxo-2,3-dihydro-1H-indole-1-carboxylic acid (Compound 8E)
本品由化合物 8D的粗产品和三氯化铝按照化合物 5A的制备方法合成，该产物不经纯化， 直接用于下一步反应。  This product was synthesized from the crude product of the compound 8D and aluminum trichloride according to the preparation method of the compound 5A, and the product was directly used for the next reaction without purification.
4-氟 -7-氯 -3-氧代 -2,3-二氢 -1H-茚 -1-甲酸甲酯 （化合物 8F)  4-fluoro-7-chloro-3-oxo-2,3-dihydro-1H-indole-1-carboxylate (Compound 8F)
本品由化合物 8E和甲醇按照化合物 5B的制备方法合成， 收率 67%。  This product was synthesized from Compound 8E and methanol according to the preparation method of Compound 5B in a yield of 67%.
4-氟 -7-氯 -3-肟 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 8G)  4-fluoro-7-chloro-3-indole-2,3-dihydro-1H-indole methyl formate (compound 8G)
本品由盐酸羟胺和化合物 8F按照化合物 5C的制备方法合成， 100%收率。  This product is synthesized from hydroxylamine hydrochloride and compound 8F according to the preparation method of compound 5C, 100% yield.
4-氟 -3-氨基 -2,3-二氢 -1H-茚小甲酸甲酯的盐酸盐 （化合物 8H) 本品由化合物 8G和浓盐酸按照化合物 5D的制备方法合成，还原氢化条件为 60 psi， 75% 收率。 Hydrochloride of 4-fluoro-3-amino-2,3-dihydro-1H-indole methyl formate (compound 8H) This product is synthesized from compound 8G and concentrated hydrochloric acid according to the preparation method of compound 5D, and the reduction hydrogenation condition is 60 psi, 75% yield.
4-氟 -3-氨基 -2,3-二氢 -1H-茚小甲酸的盐酸盐 （化合物 81)  Hydrochloride of 4-fluoro-3-amino-2,3-dihydro-1H-indolemic acid (Compound 81)
本品由化合物 8H按照化合物 5E的制备方法合成， 该粗产物不经纯化， 直接用于下一步 反应。  This product was synthesized from the compound 8H according to the preparation method of the compound 5E, and the crude product was directly used for the next reaction without purification.
8-氟 -1,2-二氢 -1，4亚甲基异喹啉 -3(4氢) -酮 （化合物 8J)  8-fluoro-1,2-dihydro-1,4-methyleneisoquinoline-3(4-hydro)-one (Compound 8J)
本品由化合物 81和二环己基碳二亚胺按照化合物 5F的制备方法合成， 四步收率 37%。 8-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉 （化合物 8K)  This product is synthesized from compound 81 and dicyclohexylcarbodiimide according to the preparation method of compound 5F, and the yield in four steps is 37%. 8-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (compound 8K)
本品由化合物 8J按照化合物 5G的制备方法合成，该产物不经纯化直接用于下一步反应。 N-(4-(8-氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化 合物 8)  This product was synthesized from the compound 8J according to the preparation method of the compound 5G, and the product was used in the next reaction without purification. N-(4-(8-fluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3 -dimethylbutyramide (compound 8)
本品由化合物 8K (300 mg， 1.83 mmol) ， N- (4-溴代 -2,6-二甲基苯基） -3-甲基丁酰胺 及叔丁醇钾按照化合物 5的制备方法合成， 43%收率。 1H NMR (400 MHz, DMSO) δ: 8.76 (s, 1H), 7.15-7.17(m, 1H)， 7.10-7.15(m, 1H)， 6.87 (t, J = 8.4 Hz, 1H), 6.38 (s, 2H), 5.26 (s, 1H), 3.82 (dd， J = 2.8， J = 8 Hz, 1H)， 3.74 (s, 1H)， 2.27 (d， J = 8.4 Hz, 1H)， 2.10-2.19 (m， 3H), 2.01 (s, 6H) 1.91 (d, J= 8.4 Hz, 1H), 1.02 (s， 9H).  This product is synthesized from compound 8K (300 mg, 1.83 mmol), N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide and potassium t-butoxide according to the preparation method of compound 5. , 43% yield. 1H NMR (400 MHz, DMSO) δ: 8.76 (s, 1H), 7.15-7.17 (m, 1H), 7.10-7.15 (m, 1H), 6.87 (t, J = 8.4 Hz, 1H), 6.38 (s , 2H), 5.26 (s, 1H), 3.82 (dd, J = 2.8, J = 8 Hz, 1H), 3.74 (s, 1H), 2.27 (d, J = 8.4 Hz, 1H), 2.10-2.19 ( m, 3H), 2.01 (s, 6H) 1.91 (d, J= 8.4 Hz, 1H), 1.02 (s, 9H).
实施例九  Example nine
N- (2，6-二甲基 -4- (6-甲基 -3，4-二氢 -1，4-亚甲基异喹啉 -2 ( 1H) -基） 苯基） -3,3-二甲基 丁酰胺的制备  N-(2,6-Dimethyl-4-(6-methyl-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)phenyl)-3, Preparation of 3-dimethylbutyramide
Figure imgf000033_0001
Figure imgf000033_0001
6—甲基—3—氧代—2,3-二氢 -1H-茚小甲酸 （化合物 9A)  6-Methyl-3-oxo-2,3-dihydro-1H-indolemic acid (Compound 9A)
本品由 3- (3-甲基苯基） 丁二酸酐按照化合物 5A的制备方法合成。  This product was synthesized from 3-(3-methylphenyl) succinic anhydride according to the preparation method of Compound 5A.
6—甲基—3—氧代—2,3-二氢 -1H-茚小甲酸甲酯 （化合物 9B)  6-Methyl-3-oxo-2,3-dihydro-1H-indole methyl formate (Compound 9B)
本品由化合物 9A按照化合物 5B的制备方法合成。  This product was synthesized from Compound 9A according to the preparation method of Compound 5B.
6-甲基 -3-肟 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 9C) 本品由化合物 9B按照化合物 5C的制备方法合成， 92%收率。 6-Methyl-3-indole-2,3-dihydro-1H-indole methyl formate (Compound 9C) This product was synthesized from the compound 9B according to the preparation method of the compound 5C, 92% yield.
6-甲基 -3-氨基 -2,3-二氢 -1H-茚小甲酸甲酯的盐酸盐 （化合物 9D)  Hydrochloride of 6-methyl-3-amino-2,3-dihydro-1H-indole methyl formate (Compound 9D)
本品由化合物 9C按照化合物 5D的制备方法合成。  This product was synthesized from Compound 9C according to the preparation method of Compound 5D.
6-甲基 -3-氨基 -2,3-二氢 -1H-茚小甲酸的盐酸盐 （化合物 9E)  Hydrochloride of 6-methyl-3-amino-2,3-dihydro-1H-indolemic acid (Compound 9E)
本品由化合物 9D按照化合物 5E的制备方法合成。  This product was synthesized from Compound 9D according to the preparation method of Compound 5E.
6-甲基 -1,2-二氢 -1,4-亚甲基异喹啉 -3 (4H) -酮 （化合物 9F)  6-Methyl-1,2-dihydro-1,4-methyleneisoquinoline-3(4H)-one (Compound 9F)
本品由化合物 9E按照化合物 5F的制备方法合成。  This product is synthesized from the compound 9E according to the preparation method of the compound 5F.
6-甲基 -1，2，3，4-四氢 -1,4-异喹啉 （化合物 9G)  6-Methyl-1,2,3,4-tetrahydro-1,4-isoquinoline (Compound 9G)
本品由化合物 9F按照化合物 5G的制备方法合成。  This product was synthesized from the compound 9F according to the preparation method of the compound 5G.
N- (2,6-二甲基 -4- (6-甲基 -3,4-二氢 -1,4-亚甲基异喹啉 -2 ( 1H) -基） 苯基） -3,3-二甲基 丁酰胺 （化合物 9)  N-(2,6-Dimethyl-4-(6-methyl-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)phenyl)-3, 3-dimethylbutyramide (compound 9)
本品由化合物 9G和 N- (4-溴代 -2,6-二甲基苯基） -3-甲基丁酰胺按照化合物 5的制备方 法合成。 1H NMR (400 MHz, CDC13) δ: 7.16 (d， J= 7.2 Hz, 1H), 7.09(s, 1H)， 6.86(d， J= 7.2 Hz 1H)， 6.43 (s, 1H), 6.36 (s, 2H), 4.92 (s, 1H), 3.82 (dd, J= 2.8， J= 8.0 Hz, 1H), 3.74 (s, 1H), 2.27 (d, J= 8.4 Hz, 1H), 2.24 (s， 3H), 2.10-2.19 (m， 2H), 2.01 (s， 6H) 1.86 (d, J= 8.4 Hz, 1H), 1.00 (s， 9H). This product was synthesized from Compound 9G and N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide according to the preparation method of Compound 5. 1H NMR (400 MHz, CDC1 3 ) δ: 7.16 (d, J = 7.2 Hz, 1H), 7.09 (s, 1H), 6.86 (d, J = 7.2 Hz 1H), 6.43 (s, 1H), 6.36 ( s, 2H), 4.92 (s, 1H), 3.82 (dd, J= 2.8, J= 8.0 Hz, 1H), 3.74 (s, 1H), 2.27 (d, J= 8.4 Hz, 1H), 2.24 (s , 3H), 2.10-2.19 (m, 2H), 2.01 (s, 6H) 1.86 (d, J= 8.4 Hz, 1H), 1.00 (s, 9H).
实施例十  Example ten
N-(4-(6-三氟甲氧基 -3，4-二氢 -1，4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基 丁酰胺的制备 N- (4-(6-trifluoromethoxy-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl Preparation of -3,3-dimethylbutyramide
Figure imgf000034_0001
Figure imgf000034_0001
2- (3-三氟甲氧基苯基） 乙酸乙酯 （化合物 10A)  2-(3-Trifluoromethoxyphenyl)acetate (Compound 10A)
本品由 3-三氟甲氧基苯乙酸和乙醇按照化合物 5B的制备方法合成， 96%收率。  This product is synthesized from 3-trifluoromethoxyphenylacetic acid and ethanol according to the preparation method of compound 5B, 96% yield.
2-二甲基- (3-三氟甲氧基苯基） 丁二酸二乙酯 （化合物 10B)  2-Dimethyl-(3-trifluoromethoxyphenyl) succinate (Compound 10B)
本品由化合物 10A和溴乙酸乙酯按照化合物 6B的制备方法合成， 99%产率。 2- (3-三氟甲氧基苯基） 丁二酸 （化合物 10C) This product was synthesized from Compound 10A and ethyl bromoacetate according to the preparation method of Compound 6B, yield 99%. 2-(3-Trifluoromethoxyphenyl) succinic acid (Compound 10C)
本品由化合物 10B和氢氧化钾按照化合物 6C的制备方法合成。  This product was synthesized from Compound 10B and potassium hydroxide according to the preparation method of Compound 6C.
3- (3-三氟甲氧基苯基） 丁二酸酐 （化合物 10D)  3-(3-Trifluoromethoxyphenyl) succinic anhydride (Compound 10D)
本品由化合物 10C、乙酰氯和氯化亚砜按照化合物 6D的制备方法合成，该化合物不经纯 化， 直接用于下一步反应。  This product was synthesized from Compound 10C, acetyl chloride and thionyl chloride according to the preparation method of Compound 6D. This compound was used in the next step without purification.
6-三氟甲氧基 -3-羰基 -2,3-二氢 -1氢-茚 -1-甲酸 （化合物 10E)  6-Trifluoromethoxy-3-carbonyl-2,3-dihydro-1hydrogen-oxime-1-carboxylic acid (Compound 10E)
本品由化合物 10D的粗产品按照化合物 5A的制备方法合成。  This product was synthesized from the crude product of Compound 10D according to the preparation method of Compound 5A.
6-三氟甲氧基 -3-羰基 -2,3-二氢 -1氢-茚小甲酸甲酯 （化合物 10F)  6-Trifluoromethoxy-3-carbonyl-2,3-dihydro-1hydrogen-hydrazide methyl formate (Compound 10F)
本品由化合物 10E按照化合物 5B的制备方法合成。  This product was synthesized from Compound 10E according to the preparation method of Compound 5B.
6-三氟甲氧基 -3-肟 -2,3-二氢 -1氢-茚小甲酸甲酯 （化合物 10G)  6-Trifluoromethoxy-3-indol-2,3-dihydro-1hydrogen-hydrazide methyl formate (Compound 10G)
本品由化合物 10F按照化合物 5C的制备方法合成， 92%收率。  This product was synthesized from the compound 10F according to the preparation method of the compound 5C, with a yield of 92%.
6-三氟甲氧基 -3-氨基 -2,3-二氢 -1氢-茚小甲酸甲酯的盐酸盐 （化合物 10H)  Hydrochloride of 6-trifluoromethoxy-3-amino-2,3-dihydro-1hydrogen-hydrazide methyl formate (Compound 10H)
本品由化合物 10G按照化合物 5D的制备方法合成。  This product was synthesized from Compound 10G according to the preparation method of Compound 5D.
6-三氟甲氧基 -3-氨基 -2,3-二氢 -1氢-茚 -1-甲酸的盐酸盐 （化合物 101)  6-Trifluoromethoxy-3-amino-2,3-dihydro-1hydrogen-hydrazide-1-carboxylic acid hydrochloride (Compound 101)
本品由化合物 10H按照化合物 5E的制备方法合成。  This product was synthesized from the compound 10H according to the preparation method of the compound 5E.
6-三氟甲氧基 -1,2-二氢 -1,4-亚甲基异喹啉 -3(4H)-酮 （化合物 10J)  6-Trifluoromethoxy-1,2-dihydro-1,4-methyleneisoquinoline-3(4H)-one (Compound 10J)
本品由化合物 101按照化合物 5F的制备方法合成。  This product was synthesized from Compound 101 according to the preparation method of Compound 5F.
6-三氟甲氧基 -1，2，3，4-四氟 -1,4-亚甲基异喹啉 （化合物 10K)  6-Trifluoromethoxy-1,2,3,4-tetrafluoro-1,4-methyleneisoquinoline (Compound 10K)
本品由化合物 10J按照化合物 5G的制备方法合成。  This product was synthesized from Compound 10J according to the preparation method of Compound 5G.
N-(4-(6-三氟甲氧基 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基 丁酰胺 （化合物 10) N- (4-(6-trifluoromethoxy-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl ) -3,3-dimethylbutyramide (compound 10)
本品由化合物 10K按照化合物 5的制备方法合成。 MS: 477 (M+H+). 1H NMR (400 MHz, CDCls) δ: 7.25 (s， 1H), 7.18 (m， 1H)6.97 (m， 1H), 6.59 (s， 1H), 6.33 (s， 2H), 4.12-4.08 (m， 1H)， 3.82 (s， 1H), 2.66 (d, J = 9.3 Hz, 1H), 2.43 (d, J = 9.3 Hz, 1H), 2.28 (s， 2H), 2.12 (s， 6H)， 1.12 (s， 9H)， 0.97 (s, 1H). This product is synthesized from the compound 10K according to the preparation method of the compound 5. MS: 477 (M+H + ). 1H NMR (400 MHz, CDCls) δ: 7.25 (s, 1H), 7.18 (m, 1H) 6.97 (m, 1H), 6.59 (s, 1H), 6.33 (s , 2H), 4.12-4.08 (m, 1H), 3.82 (s, 1H), 2.66 (d, J = 9.3 Hz, 1H), 2.43 (d, J = 9.3 Hz, 1H), 2.28 (s, 2H) , 2.12 (s, 6H), 1.12 (s, 9H), 0.97 (s, 1H).
实施例 ^一  Example ^1
N-(4-(6，8-二氟 -3，4-二氢 -1，4-亚甲基异喹啉 -2(1氢) -基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺 的制备 N-(4-(6,8-Difluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl) Preparation of -3,3-dimethylbutanamide
Figure imgf000036_0001
Figure imgf000036_0001
2- (3， 5-二氟苯基） 乙酸乙酯 （化合物 11A)  2-(3, 5-Difluorophenyl)acetate (Compound 11A)
本品由 3， 5-二氟苯乙酸和乙醇按照化合物 5B的制备方法合成， 该粗产物不经纯化， 直 接用于下一步反应。  This product is synthesized from 3, 5-difluorophenylacetic acid and ethanol according to the preparation method of compound 5B. The crude product is used in the next step without purification.
2—二甲基- (3, 5-二氟苯基） 丁二酸二乙酯 （化合物 11B)  2-Dimethyl-(3, 5-difluorophenyl) diethyl succinate (Compound 11B)
本品由化合物 11A和溴乙酸乙酯按照化合物 6B的制备方法合成， 两步产率 87%。 This product was synthesized from Compound 11A and ethyl bromoacetate according to the preparation of Compound 6B. The yield in two steps was 87%.
2- (3， 5-二氟苯基） 丁二酸 （化合物 11C) 2-(3, 5-difluorophenyl) succinic acid (Compound 11C)
本品由化合物 11B和氢氧化钾按照化合物 6C的制备方法合成， 该粗产物不经纯化， 直 接用于下一步反应。  This product was synthesized from Compound 11B and potassium hydroxide according to the preparation of Compound 6C. This crude product was used in the next step without purification.
3- (3， 5-二氟苯基） 丁二酸酐 （化合物 11D)  3-(3, 5-difluorophenyl) succinic anhydride (Compound 11D)
本品由化合物 11C、乙酰氯和氯化亚砜按照化合物 6D的制备方法合成，粗产物不经纯化 直接用于下一步反应。  This product was synthesized from compound 11C, acetyl chloride and thionyl chloride according to the preparation method of compound 6D, and the crude product was used in the next reaction without purification.
4， 6-二氟 -3-氧代 -2,3-二氢 -1氢-茚小甲酸 （化合物 11E)  4,6-Difluoro-3-oxo-2,3-dihydro-1hydrogen-hydrazine carboxylic acid (Compound 11E)
本品由化合物 11D的粗产品按照化合物 5A的制备方法合成。  This product was synthesized from the crude product of Compound 11D according to the preparation method of Compound 5A.
4， 6-二氟 -3-氧代 -2,3-二氢 -1氢-茚 -1-甲酸甲酯 （化合物 11F)  4,6-Difluoro-3-oxo-2,3-dihydro-l-hydrogen-indole-1-methylcarboxylate (Compound 11F)
本品由化合物 11E按照化合物 5B的制备方法合成。  This product was synthesized from Compound 11E according to the preparation method of Compound 5B.
4， 6-二氟 -3-肟 -2,3-二氢 -1氢-茚小甲酸甲酯 （化合物 11G)  4,6-Difluoro-3-indole-2,3-dihydro-1hydrogen-hydrazide methyl formate (Compound 11G)
本品由化合物 11F按照化合物 5C的制备方法合成。  This product was synthesized from Compound 11F according to the preparation method of Compound 5C.
4， 6-二氟 -3-氨基 -2,3-二氢 -1氢-茚小甲酸甲酯的盐酸盐 （化合物 11H)  Hydrochloride of 4,6-difluoro-3-amino-2,3-dihydro-1hydrogen-hydrazide methyl formate (Compound 11H)
本品由化合物 11G按照化合物 5D的制备方法合成。  This product was synthesized from Compound 11G according to the preparation method of Compound 5D.
4， 6-二氟 -3-氨基 -2,3-二氢 -1氢-茚 -1-甲酸的盐酸盐 （化合物 111)  Hydrochloride salt of 4,6-difluoro-3-amino-2,3-dihydro-1hydrogen-indole-1-carboxylate (Compound 111)
本品由化合物 11H按照化合物 5E的制备方法合成。  This product was synthesized from Compound 11H according to the preparation method of Compound 5E.
6， 8-二氟 -1,2-二氢 -1,4-亚甲基异喹啉 -3(4H)-酮 （化合物 11J) 本品由化合物 111按照化合物 5F的制备方法合成。 6, 8-difluoro-1,2-dihydro-1,4-methylene isoquinoline-3(4H)-one (Compound 11J) This product was synthesized from Compound 111 according to the preparation method of Compound 5F.
6,8-二氟 -1，2，3，4-四氟 -1,4-亚甲基异喹啉 （化合物 11K)  6,8-Difluoro-1,2,3,4-tetrafluoro-1,4-methyleneisoquinoline (Compound 11K)
本品由化合物 11J按照化合物 5G的制备方法合成。  This product was synthesized from Compound 11J according to the preparation method of Compound 5G.
N-(4-(6，8-二氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 (化合物 11 )  N-(4-(6,8-Difluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl) -3,3-dimethylbutyramide (compound 11)
本品由化合物 11K按照化合物 5的制备方法合成，收率 55%。1H NMR (400 MHz, DMSO) δ: 8.78(s, 1H)， 7.10(dd, J = 2 Hz, J = 7.6 Hz, 1H)， 6.84-6.90(m, 1H)， 6.38(s, 2H), 5.27(s, 1H)， 3.80-3.84(m, 1H), 3.75-3.78(m, 1H), 2.25-2.30(m, 1H), 2.10-2.18(m, 3H), 2.01(s, 6H)， 1.91-1.96(m: 1H), 1.02(s, 9H). This product was synthesized from the compound 11K according to the preparation method of the compound 5 in a yield of 55%. 1H NMR (400 MHz, DMSO) δ: 8.78 (s, 1H), 7.10 (dd, J = 2 Hz, J = 7.6 Hz, 1H), 6.84-6.90 (m, 1H), 6.38 (s, 2H), 5.27(s, 1H), 3.80-3.84(m, 1H), 3.75-3.78(m, 1H), 2.25-2.30(m, 1H), 2.10-2.18(m, 3H), 2.01(s, 6H), 1.91-1.96 (m : 1H), 1.02 (s, 9H).
实施例十二  Example twelve
N-(4-(5，8-二氟 -3，4-二氢 -1，4-亚甲基异喹啉 -2(1氢) -基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺 的制备  N-(4-(5,8-Difluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl) Preparation of -3,3-dimethylbutanamide
Figure imgf000037_0001
Figure imgf000037_0001
2- (2， 5-二氟苯基） 乙酸乙酯 （化合物 12A)  2-(2,5-difluorophenyl)acetate (Compound 12A)
本品由 2，5-二氟苯乙酸按照化合物 5B的制备方法合成。  This product is synthesized from 2,5-difluorophenylacetic acid according to the preparation method of compound 5B.
2-二甲基- (2， 5-二氟苯基） 丁二酸二乙酯 （化合物 12B)  2-Dimethyl-(2, 5-difluorophenyl) diethyl succinate (Compound 12B)
本品由化合物 12A按照化合物 6B的制备方法合成。  This product was synthesized from Compound 12A according to the preparation method of Compound 6B.
2- (2， 5-二氟苯基） 丁二酸 （化合物 12C)  2-(2, 5-difluorophenyl) succinic acid (Compound 12C)
本品由化合物 12B按照化合物 6C的制备方法合成， 收率 94%。  This product was synthesized from Compound 12B according to the preparation method of Compound 6C, yield 94%.
3- (2， 5-二氟苯基） 丁二酸酐 （化合物 12D)  3-(2,5-difluorophenyl) succinic anhydride (compound 12D)
本品由化合物 12C按照化合物 6D的制备方法合成， 粗品直接投下步反应。  This product is synthesized from the compound 12C according to the preparation method of the compound 6D, and the crude product is directly subjected to a step reaction.
3， 6-二氟 -3-氧代 -2,3-二氢 -1氢-茚小甲酸 (化合物 12E)  3,6-Difluoro-3-oxo-2,3-dihydro-1hydrogen-hydrazine carboxylic acid (Compound 12E)
本品由化合物 12D的粗产品按照化合物 5A的制备方法合成， 两步收率 90%。  This product is synthesized from the crude product of compound 12D according to the preparation method of compound 5A, and the yield in two steps is 90%.
3， 6-二氟 -3-氧代 -2,3-二氢 -1氢-茚 -1-甲酸甲酯 （化合物 12F) 本品由化合物 12E按照化合物 5B的制备方法合成， 68%收率。 Methyl 3,6-difluoro-3-oxo-2,3-dihydro-1hydro-indole-1-carboxylate (Compound 12F) This product was synthesized from Compound 12E according to the preparation method of Compound 5B, yield 68%.
3， 6-二氟 -3-肟 -2,3-二氢 -1氢-茚小甲酸甲酯 （化合物 12G)  3,6-Difluoro-3-indole-2,3-dihydro-1hydrogen-hydrazide methyl formate (Compound 12G)
本品由化合物 12F按照化合物 5C的制备方法合成， 95%收率。  This product was synthesized from the compound 12F according to the preparation method of the compound 5C, 95% yield.
3， 6-二氟 -3-氨基 -2,3-二氢 -1氢-茚 -1-甲酸甲酯的盐酸盐 （化合物 12H)  Hydrochloride of 3,6-difluoro-3-amino-2,3-dihydro-l-hydrogen-indole-1-carboxylate (Compound 12H)
本品由化合物 12G按照化合物 5D的制备方法合成， 70%收率。  This product was synthesized from the compound 12G according to the preparation method of the compound 5D, 70% yield.
3， 6-二氟 -3-氨基 -2,3-二氢 -1氢-茚 -1-甲酸的盐酸盐 （化合物 121)  3,6-Difluoro-3-amino-2,3-dihydro-1hydrogen-hydrazide-1-carboxylic acid hydrochloride (Compound 121)
本品由化合物 12H按照化合物 5E的制备方法合成， 88%收率。  This product was synthesized from the compound 12H according to the preparation method of the compound 5E, 88% yield.
5，8-二氟 -1,2-二氢 -1,4-亚甲基异喹啉 -3(4H)-酮 （化合物 12J)  5,8-Difluoro-1,2-dihydro-1,4-methyleneisoquinoline-3(4H)-one (Compound 12J)
本品由化合物 121按照化合物 5F的制备方法合成。  This product was synthesized from Compound 121 according to the preparation method of Compound 5F.
5，8-二氟 -1，2，3，4-四氟 -1,4-亚甲基异喹啉 （化合物 12K)  5,8-Difluoro-1,2,3,4-tetrafluoro-1,4-methyleneisoquinoline (Compound 12K)
本品由化合物 12J按照化合物 5G的制备方法合成。  This product was synthesized from Compound 12J according to the preparation method of Compound 5G.
N-(4-(5，8-二氟 -3,4-二氢 -1,4-亚甲基异喹啉 -2(1氢) -基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 (化合物 12)  N-(4-(5,8-Difluoro-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-dimethylphenyl) -3,3-dimethylbutyramide (compound 12)
本品由化合物 12K按照化合物 5的制备方法合成， 40%收率。 MS: 399(M+H+).1H NMR (400 MHz, DMSO) δ: 8.79 (s, 1H), 6.96(m， 2H)， 6.40(s, 2H)， 5.33 (s, 1H), 3.94 (s, 1H), 3.84 (dd， J = 2.8, J= 8 Hz, 1H), 3.74 (s， 1H), 2.27 (d, J= 8.4 Hz, 1H), 2.10-2.19 (m， 3H), 2.02 (s， 6H) 1.91 (d， J= 8.4 Hz, 1H)， 1.03 (s, 9H). This product was synthesized from the compound 12K according to the preparation method of the compound 5, 40% yield. MS: 399 (M+H + ).1H NMR (400 MHz, DMSO) δ: 8.79 (s, 1H), 6.96 (m, 2H), 6.40 (s, 2H), 5.33 (s, 1H), 3.94 ( s, 1H), 3.84 (dd, J = 2.8, J= 8 Hz, 1H), 3.74 (s, 1H), 2.27 (d, J= 8.4 Hz, 1H), 2.10-2.19 (m, 3H), 2.02 (s, 6H) 1.91 (d, J= 8.4 Hz, 1H), 1.03 (s, 9H).
实施例十三  Example thirteen
N- (2，6-二甲基 -4- ( 8-甲基 -3，4-二氢 -1，4-亚甲基异喹啉 -2 ( 1H) -基） 苯基） -3,3-二甲基 丁酰胺的制备  N-(2,6-Dimethyl-4-(8-methyl-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)phenyl)-3, Preparation of 3-dimethylbutyramide
Figure imgf000038_0001
Figure imgf000038_0001
4-甲基 -3-氧代 -2,3-二氢 -1H-茚小甲酸 （化合物 13A)  4-methyl-3-oxo-2,3-dihydro-1H-indolemic acid (Compound 13A)
本品由 3- (3-甲基苯基） 丁二酸酐按照化合物 5A的制备方法合成。  This product was synthesized from 3-(3-methylphenyl) succinic anhydride according to the preparation method of Compound 5A.
4-甲基 -3-氧代 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 13B)  4-methyl-3-oxo-2,3-dihydro-1H-indole methyl formate (Compound 13B)
本品由化合物 13A按照化合物 5B的制备方法合成， 收率 67%。  This product was synthesized from Compound 13A according to the preparation method of Compound 5B in a yield of 67%.
4-甲基 -3-肟 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 13C) 本品由化合物 13B按照化合物 5C的制备方法合成， 92%收率。 4-methyl-3-indol-2,3-dihydro-1H-indole methyl formate (compound 13C) This product was synthesized from the compound 13B according to the preparation method of the compound 5C, with a yield of 92%.
4-甲基 -3-氨基 -2,3-二氢 -1H-茚小甲酸甲酯的盐酸盐 （化合物 13D)  Hydrochloride of 4-methyl-3-amino-2,3-dihydro-1H-indole methyl formate (Compound 13D)
本品由化合物 13C按照化合物 5D的制备方法合成。  This product was synthesized from Compound 13C according to the preparation method of Compound 5D.
4-甲基 -3-氨基 -2,3-二氢 -1H-茚小甲酸的盐酸盐 （化合物 13E)  Hydrochloride of 4-methyl-3-amino-2,3-dihydro-1H-indolemic acid (Compound 13E)
本品由化合物 13D按照化合物 5E的制备方法合成。  This product was synthesized from Compound 13D according to the preparation method of Compound 5E.
8-甲基 -1,2-二氢 -1,4-亚甲基异喹啉 -3 (4H) -酮 （化合物 13F)  8-methyl-1,2-dihydro-1,4-methyleneisoquinoline-3(4H)-one (Compound 13F)
本品由化合物 13E按照化合物 5F的制备方法合成。  This product was synthesized from Compound 13E according to the preparation method of Compound 5F.
8-甲基 -1，2，3，4-四氢 -1,4-亚甲基异喹啉 （化合物 13G)  8-methyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (compound 13G)
本品由化合物 13F按照化合物 5G的制备方法合成， 79% 产率。  This product was synthesized from the compound 13F according to the preparation method of the compound 5G in a yield of 79%.
N- (2,6-二甲基 -4- ( 8-甲基 -3,4-二氢 -1,4-亚甲基异喹啉 -2 ( 1H) -基） 苯基） -3,3-二甲基 丁酰胺 （化合物 13 )  N-(2,6-Dimethyl-4-(8-methyl-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)phenyl)-3, 3-dimethylbutyramide (compound 13)
本品由化合物 13G按照化合物 5的制备方法合成， 26% 收率。 MS: 377.2 (M+H+).1H NMR (400 MHz, CDCls) δ: 7.16 (d, J= 7.2 Hz, 1H), 7.09(s, 1H)， 6.86(d， J= 7.2 Hz 1H)， 6.43 (s， 1H)， 6.36 (s, 2H), 4.92 (s, 1H)， 3.82 (dd， J= 2.8, J= 8.0 Hz, 1H)， 3.74 (s, 1H)， 2.27 (d, J= 8.4 Hz, 1H)， 2.24 (s, 3H), 2.10-2.19 (m， 2H), 2.01 (s, 6H) 1.86 (d, J= 8.4 Hz, 1H), 1.00 (s, 9H). This product was synthesized from the compound 13G according to the preparation method of the compound 5 in 26% yield. MS: 377.2 (M+H + ).1H NMR (400 MHz, CDCls) δ: 7.16 (d, J = 7.2 Hz, 1H), 7.09 (s, 1H), 6.86 (d, J = 7.2 Hz 1H), 6.43 (s, 1H), 6.36 (s, 2H), 4.92 (s, 1H), 3.82 (dd, J= 2.8, J= 8.0 Hz, 1H), 3.74 (s, 1H), 2.27 (d, J= 8.4 Hz, 1H), 2.24 (s, 3H), 2.10-2.19 (m, 2H), 2.01 (s, 6H) 1.86 (d, J= 8.4 Hz, 1H), 1.00 (s, 9H).
实施例十四  Embodiment 14
N- (2，6-二甲基 -4- ( 1，2，3，4-四氢-1，4- (桥亚甲胺) 萘 -10-基) 苯基） -3,3-二甲基丁酰胺的 制备  N-(2,6-Dimethyl-4-( 1,2,3,4-tetrahydro-1,4-(bridgedmethyleneamine)naphthalen-10-yl)phenyl)-3,3-di Preparation of methylbutyric acid
Figure imgf000039_0001
Figure imgf000039_0001
1-乙酯 -5-甲酯 -2-苯戊二酸 （化合物 14A)  1-ethyl ester -5-methyl ester-2-phenylglutaric acid (compound 14A)
将苯乙酸乙酯 （35g， 213 mmol) 溶于甲苯 （30 mL) ， 在氮气保护下于 -78 °C下滴入叔 丁醇钾 （6.2 g， 55.4 mmol) 的甲苯（50 mL)溶液中。 15分钟后滴加入 18-冠 -6-醚 （2.82 g， 10.7 mmol) 的甲苯 （50 mL) 溶液， 15分钟后加入丙烯酸甲酯 （1.22 mL) 的甲苯 （5 mL) 溶液。 在 -78°C下搅拌半小时后将反应液导入饱和氯化铵溶液（40 mL) ， 用乙酸乙酯萃取 （3 X 50 mL) ， 饱和食盐水洗， 无水硫酸钠干燥， 旋干后用石油醚 /乙酸乙酯 = 50/1， 纯化得到 目标化合物 （25.7 g， 49% 收率） 。 2-苯基戊二酸 （化合物 14B) Ethyl phenylacetate (35 g, 213 mmol) was dissolved in toluene (30 mL), and a solution of potassium t-butoxide (6.2 g, 55.4 mmol) in toluene (50 mL) was added dropwise at -78 °C under nitrogen atmosphere. . After 15 minutes, a solution of 18-crown-6-ether (2.82 g, 10.7 mmol) in toluene (50 mL) was added dropwise, and after 15 minutes, a solution of methyl acrylate (1.22 mL) in toluene (5 mL) was added. After stirring at -78 ° C for half an hour, the reaction solution was poured into a saturated ammonium chloride solution (40 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried over anhydrous sodium sulfate The title compound (25.7 g, 49% yield) was obtained after purification of petroleum ether / ethyl acetate = 50/1. 2-phenylglutaric acid (compound 14B)
本品由化合物 14A和氢氧化钾按照化合物 6C的制备方法合成， 98% 收率。  This product was synthesized from Compound 14A and potassium hydroxide according to the preparation method of Compound 6C, 98% yield.
3-苯基二氢呋喃 -2,5-二酮 （化合物 14C)  3-phenyldihydrofuran-2,5-dione (compound 14C)
本品由化合物 14B、 二氯亚砜和乙酰氯按照化合物 6D的制备方法合成。  This product is synthesized from the compound 14B, dichlorosulfoxide and acetyl chloride according to the preparation method of the compound 6D.
4-羰基 -1，2，3，4-四氢萘 -1-甲酸 （化合物 14D)  4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Compound 14D)
本品由化合物 14C按照化合物 5A的制备方法合成， 49%收率。  This product was synthesized from the compound 14C according to the preparation method of the compound 5A, yield 49%.
4-幾基 -1，2，3，4-四氢萘 -1-甲酸甲酯 （化合物 14E)  4-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (Compound 14E)
本品由化合物 14D按照化合物 5B的制备方法合成， 67%收率。  This product was synthesized from Compound 14D according to the method for the preparation of Compound 5B, yield 67%.
4-肟 -1，2，3，4-四氢萘 -1-甲酸甲酯 （化合物 14F)  4-肟 -1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (Compound 14F)
本品由化合物 14E按照化合物 5C的制备方法合成， 98%收率。  This product was synthesized from Compound 14E according to the method for the preparation of Compound 5C, 98% yield.
4-氨基 -1，2，3，4-四氢萘 -1-甲酸甲酯的盐酸盐 （化合物 14G)  Hydrochloride of 4-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Compound 14G)
本品由化合物 14F按照化合物 5D的制备方法合成， 75%收率。  This product was synthesized from Compound 14F according to the preparation method of Compound 5D, 75% yield.
4-氨基 -1，2，3，4-四氢萘 -1-甲酸的盐酸盐 （化合物 14H)  4-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid hydrochloride (Compound 14H)
本品由化合物 14G按照化合物 5E的制备方法合成， 82%收率。  This product was synthesized from the compound 14G according to the preparation method of the compound 5E, 82% yield.
1，2，3，4-四氢 -1,4- (桥亚甲胺) 萘 -9-酮 (化合物 141)  1,2,3,4-tetrahydro-1,4-(methyleneamine)naphthalene-9-one (compound 141)
本品由化合物 14H按照化合物 5F的制备方法合成。  This product is synthesized from the compound 14H according to the preparation method of the compound 5F.
1，2，3，4-四氢 -1,4- (桥亚甲胺) 萘 (化合物 14J)  1,2,3,4-tetrahydro-1,4-(methyleneamine) naphthalene (compound 14J)
本品由化合物 141按照化合物 5G的制备方法合成。  This product was synthesized from Compound 141 according to the preparation method of Compound 5G.
N- (2,6-二甲基 -4- ( 1，2，3，4-四氢 -1,4- (桥亚甲胺)萘 -10-基)苯基） -3,3-二甲基丁酰胺（化 合物 14)  N-(2,6-Dimethyl-4-(1,2,3,4-tetrahydro-1,4-(bridgedmethyleneamine)naphthalen-10-yl)phenyl)-3,3-di Methyl butyramide (compound 14)
本品由化合物 14J按照化合物 5的制备方法合成， 8%收率。 MS: 377 (M+H+). This product was synthesized from the compound 14J according to the preparation method of the compound 5, 8% yield. MS: 377 (M+H + ).
1H NMR (400 MHz, CDC13) δ: 8.80 (s， IH), 7.36-7.34 (m， IH)， 7.34-7.31 (m, IH)， 7.24-7.20 (m, 2H), 6.44 (s, 2H), 5.05 (s, 1H)， 3.49 (dd, J= 1.2, J= 8.8 Hz, IH), 3.32 (s, 1H)， 2.84 (d， J= 9.2 Hz, IH), 2.14 (s, 3H), 2.05 (s, 6H)， 1.92-1.89 (m， IH), 1.50-1.42 (m， 2H), 1.06 (s, 9H). 1H NMR (400 MHz, CDC1 3 ) δ: 8.80 (s, IH), 7.36-7.34 (m, IH), 7.34-7.31 (m, IH), 7.24-7.20 (m, 2H), 6.44 (s, 2H ), 5.05 (s, 1H), 3.49 (dd, J= 1.2, J= 8.8 Hz, IH), 3.32 (s, 1H), 2.84 (d, J= 9.2 Hz, IH), 2.14 (s, 3H) , 2.05 (s, 6H), 1.92-1.89 (m, IH), 1.50-1.42 (m, 2H), 1.06 (s, 9H).
实施例十五  Example fifteen
N-(4-(7-氟 -(2，3，4，5-四氢 -IH-苯并 [c]氮杂 -2(3H)- 基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 N-(4-(7-fluoro-(2,3,4,5-tetrahydro-IH-benzo[c]azepine-2(3H)-yl)-2,6-dimethylphenyl) -3,3-dimethylbutyramide
(化合物 15 ) 的制备
Figure imgf000041_0001
Preparation of (Compound 15)
Figure imgf000041_0001
(E)-3-(2-氰基 -5-氟苯基)丙烯酸 （化合物 15A)  (E)-3-(2-cyano-5-fluorophenyl)acrylic acid (Compound 15A)
2-溴 -4-氟苯腈 （3.06 g， 15 mmol), 丙烯酸 （3 mL， 45 mmol), 醋酸钯 （340 mg， 1.5 mmol), 三 (邻甲基苯基)磷 （684 mg， 2.25 mmol),三乙胺 （11 mL， 75 mmol)溶于 30 mL N，N-二甲基甲 酰胺中， 氮气保护下， 在 1 10 °C 反应 3 h。 用饱和碳酸钠溶液调节反应液 PH=8， 乙酸乙酯 萃取， 用 2 N 盐酸溶液调节水相 PH=6， 乙酸乙酯萃取， 水洗， 无水硫酸钠干燥， 减压旋干 溶剂得到粗产品 （2.8 g， 产率 97%)。  2-bromo-4-fluorobenzonitrile (3.06 g, 15 mmol), acrylic acid (3 mL, 45 mmol), palladium acetate (340 mg, 1.5 mmol), tris(o-methylphenyl)phosphorous (684 mg, 2.25 Methyl acetate (11 mL, 75 mmol) was dissolved in 30 mL of N,N-dimethylformamide and reacted at 10 ° C for 3 h under nitrogen. The reaction mixture was adjusted to pH = 8 with a saturated sodium carbonate solution, ethyl acetate was extracted, and the aqueous phase was adjusted to pH = 6 with 2 N hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness (2.8 g, yield 97%).
3- (2- (氨甲基) -5-氟苯基)丙酸 （化合物 15B ) 3-(2-(Aminomethyl)-5-fluorophenyl)propionic acid (Compound 15B)
EK3-C2-氰基 -5-氟苯基)丙烯酸 （1.91 g， 10 mmol)溶于 2: 1 甲醇 /28%氨水 （120 mL)， 然 后加入雷尼镍（2.00 g)，在氢气下室温反应 16 h，催化剂过滤，减压旋干溶剂得到粗产品 （1.68 g， 85% yield)。  EK3-C2-cyano-5-fluorophenyl)acrylic acid (1.91 g, 10 mmol) was dissolved in 2:1 methanol/28% aqueous ammonia (120 mL) then Raney nickel (2.00 g) was added at room temperature under hydrogen After 16 h of reaction, the catalyst was filtered, and the solvent was evaporated to dryness to give a crude product (1.68 g, 85% yield).
7-氟 -4,5-二氢 -1H-苯并 [c]氮杂环庚烯 -3 ( 2H) -酮 （化合物 15C )  7-fluoro-4,5-dihydro-1H-benzo[c]azepine-3(2H)-one (compound 15C)
3-(2- (氨甲基) -5-氟苯基)丙酸 （1.64 g， 8.24 mmol), 吡啶 （1.5 mL， 16.5 mmol) 溶于乙腈 /水 (3 : 1， 660 mL)并在冰水中 lO min后， 加入 EDC (2.1 g， 10.7 mmol), 30 min后移走冰水， 在室 温下反应 16 h， 减压旋干溶剂， 二氯甲烷萃取， 水洗， 无水硫酸钠干燥， 减压旋干溶剂， 柱 层析纯化得产物 （180 mg， 12% yield)。  3-(2-(Aminomethyl)-5-fluorophenyl)propanoic acid (1.64 g, 8.24 mmol), pyridine (1.5 mL, 16.5 mmol) dissolved in acetonitrile/water (3:1, 660 mL) After 10 min in ice water, EDC (2.1 g, 10.7 mmol) was added. After 30 min, the ice water was removed, and the mixture was reacted for 16 h at room temperature. The solvent was evaporated, evaporated, evaporated, evaporated The solvent was evaporated to dryness <RTI ID=0.0></
7-氟 -2，3，4，5-四氢 -1H-苯并 [c]氮杂 （化合物 15D )  7-fluoro-2,3,4,5-tetrahydro-1H-benzo[c]aza (compound 15D)
在 0 °C 下， 将溶有四氢锂铝 （190 mg， 5 mmol) 的四氢呋喃 （；10 mL) 溶液慢慢滴 加到溶有 7-氟 -4,5-二氢 -1H-苯并 [c]氮杂环庚烯 -3 ( 2H) -酮 （180 mg， 1 mmol) 的四氢呋喃 （20 mL) 溶液中， 滴加完毕后， 升温至回流反应 24 小时， 冷却到室温， 用 20%的氢氧化钾 溶液淬灭， 固体过滤， 有机相用无水硫酸钠干燥， 减压旋干得到无色液体 （166 mg， 产 率 99%)。  A solution of tetrahydrofuran (10 mL) in which lithium aluminum hydride (190 mg, 5 mmol) was dissolved was slowly added dropwise to dissolve 7-fluoro-4,5-dihydro-1H-benzene at 0 °C. [c]Azepine-3(2H)-one (180 mg, 1 mmol) in tetrahydrofuran (20 mL), after the dropwise addition, warmed to reflux for 24 hours, cooled to room temperature, with 20% The potassium hydroxide solution was quenched, the solid was filtered, and the organic layer was dried over anhydrous sodium sulfate.
Ν-(4-(7-氟 -(2，3，4，5-四氢 -1Η-苯并 [c]氮杂 -2(3H)- 基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 (化合物 15 )  Ν-(4-(7-fluoro-(2,3,4,5-tetrahydro-1 fluorene-benzo[c]azepine-2(3H)-yl)-2,6-dimethylphenyl) -3,3-dimethylbutyramide (compound 15)
本品由 7-氟 -2，3，4，5-四氢 -1H-苯并 [c]氮杂 （166 mg， 1 mmol)和 N- ( 4-溴代 -2,6-二甲基苯基） -3,3-二甲基丁酰胺 C360 mg， 1.2 mmol) 按照化合物 5的制备方法合成， 1 10°C 反应 4 小时， 纯化得目标产物 （60 mg， 产率 16%)。 MS: 383 (M+H+)。 iHNMR (DMSO, 400 MHz): δ 8.70 (s, 1H), 7.42-7.46 (m， 1H)， 6.95-6.98 (m， 1H)， 6.86-6.90 (m，lH)， 6.48 (s, 2H), 4.57 (s, 2H), 3.75 (s 2H), 2.95-2.97 (m， 2H), 2.11 (s， 2H), 2.00 (s， 6H)， 1.73 (s， 2H), 1.01 (s， 9H)。 This product consists of 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[c]aza (166 mg, 1 mmol) and N-(4-bromo-2,6-dimethyl Phenyl)-3,3-dimethylbutyramide C360 mg, 1.2 mmol) was synthesized according to the preparation method of compound 5, and reacted at 10 ° C for 4 hours. The title product was obtained (60 mg, yield 16%). MS: 383 (M+H + ). iHNMR (DMSO, 400 MHz): δ 8.70 (s, 1H), 7.42-7.46 (m, 1H), 6.95-6.98 (m, 1H), 6.86-6.90 (m, lH), 6.48 (s, 2H), 4.57 (s, 2H), 3.75 (s 2H), 2.95-2.97 (m, 2H), 2.11 (s, 2H), 2.00 (s, 6H), 1.73 (s, 2H), 1.01 (s, 9H).
实施例十六  Example sixteen
N-(2,6- 二甲基 -4- (哌啶 -1-基） 苯) -3,3-二甲基丁酰胺的制备
Figure imgf000042_0001
Preparation of N-(2,6-dimethyl-4-(piperidin-1-yl)benzene)-3,3-dimethylbutanamide
Figure imgf000042_0001
N-(4-溴 -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 16A)  N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 16A)
4-溴-2，6-二甲基氨（10§，0.05 1^1)和三乙胺（15.2 §，0.15 1^)1)溶于干燥的二氯甲烷， 0°C 搅拌反应 20分钟， 然后加入 8.37ml叔丁基乙酰氯， 室温搅拌反应 3小时。 反应结束加入水， 乙酸乙酯提取， 有机层用无水硫酸钠干燥， 减压浓縮。 粗品用石油醚洗涤， 得到白色固体化 合物 1A ( 12g, 81%收率） 。 4-Bromo-2,6-dimethylamino (10 § , 0.05 1^1) and triethylamine (15.2 § , 0.15 1^) 1) Dissolved in dry dichloromethane, stirred at 0 ° C for 20 minutes Then, 8.37 ml of t-butylacetyl chloride was added, and the reaction was stirred at room temperature for 3 hours. At the end of the reaction, water was added, and ethyl acetate was evaporated. The crude product was washed with EtOAc (EtOAc:EtOAc)
N-(2,6- 二甲基 -4- (哌啶 -1-基） 苯) -3,3-二甲基丁酰胺 （化合物 16)  N-(2,6-Dimethyl-4-(piperidin-1-yl)benzene)-3,3-dimethylbutanamide (Compound 16)
本品由哌啶和 N-(4-溴 -2,6-二甲基苯) -3,3-二甲基丁酰胺按照化合物 5 的制备方法合成， 35%收率。 MS: 303 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.22 (brs, 1H), 7.24 (brs, 1H)， 3.41 (s， 4H)， 2.22 (s， 2H), 2.17 (s， 6H)， 1.81 (s， 4H)， 1.62 (brs, 2H), 1.06 (s， 9H). This product is synthesized from piperidine and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 5, 35% yield. MS: 303 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.22 (brs, 1H), 7.24 (brs, 1H), 3.41 (s, 4H), 2.22 (s, 2H), 2.17 (s, 6H), 1.81 (s, 4H), 1.62 (brs, 2H), 1.06 (s, 9H).
实施例十七  Example seventeen
N-(4-(3，4-二氢异喹 -2(1H)-基) -2，6-二甲基苯) -3，3-二甲基丁酰胺的盐酸盐的制备
Figure imgf000042_0002
Preparation of hydrochloride salt of N-(4-(3,4-dihydroisoquino-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000042_0002
4，4-二甲基哌啶 （化合物 17A)  4,4-Dimethylpiperidine (Compound 17A)
本品由 4，4-二甲基哌啶基 -2,6-二酮按照化合物 5G的制备方法合成， 32%收率。  This product was synthesized from 4,4-dimethylpiperidinyl-2,6-dione according to the preparation method of compound 5G in 32% yield.
N-(4-(3，4-二氢异喹啉 -2(1H)-基) -2,6-二甲基苯) -3,3-二甲基丁酰胺盐酸盐 （化合物 17) 本品由化合物 17A禾 B N- (4-溴 -2， 6-二甲基苯） -3， 3-二甲基丁酰胺按照化合物 7的制 备方法合成， 15%产率。 MS:331.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.286 (s, 1Η), 7.47 (brs, 2H), 3.45 (brs, 4H)， 2.24 (s, 2H), 2.19 (s, 3H), 1.73 (brs, 4H)， 1.07(s, 15H).  N-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide hydrochloride (Compound 17) This product was synthesized from Compound 17A and B N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of Compound 7, 15% yield. MS: 331.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.286 (s, 1 Η), 7.47 (brs, 2H), 3.45 (brs, 4H), 2.24 (s, 2H), 2.19 (s, 3H), 1.73 (brs, 4H), 1.07(s, 15H).
实施例十八  Example 18
N-(2,6- 二甲基 -4- (4-哌啶酮） 苯基) -3,3-二甲基丁酰胺的制备
Figure imgf000043_0001
Preparation of N-(2,6-dimethyl-4-(4-piperidone)phenyl)-3,3-dimethylbutanamide
Figure imgf000043_0001
N-(2,6- 二甲基 -4- (4-哌啶酮縮乙二醇） 苯基) -3,3-二甲基丁酰胺 （化合物 18A) 本品由 4-哌啶酮縮乙二醇和 N-(4-溴 -2,6-二甲基苯) -3,3-二甲基丁酰胺按照化合物 5的制 备方法合成， 54%收率。 MS: 361 (M+H+). N-(2,6-Dimethyl-4-(4-piperidone ketal) phenyl)-3,3-dimethylbutanamide (Compound 18A) This product is 4-piperidone Ethylene glycol and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide were synthesized according to the preparation method of compound 5, 54% yield. MS: 361 (M+H + ).
N-(2,6- 二甲基 -4- (4-哌啶酮） 苯基) -3,3-二甲基丁酰胺 （化合物 18)  N-(2,6-Dimethyl-4-(4-piperidone)phenyl)-3,3-dimethylbutanamide (Compound 18)
将化合物 18A溶于丙酮-水 （10 mL-5 mL) ， 于封管中 80°C搅拌 24小时， 然后旋干， 制 备得白色固体化合物 18 (30 mg, 12%收率）。 MS: 317 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.90 (brs, 1H), 6.74 (s， 2H), 3.58-3.55 (m， 4H)， 2.40-2.37 (m， 4H)， 2.17 (s， 2H), 2.10 (s， 6H)，The compound 18A was dissolved in acetone-water (10 mL - 5 mL), and the mixture was stirred at 80 ° C for 24 hrs, and then dried to give a white solid compound 18 (30 mg, 12% yield). MS: 317 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.90 (brs, 1H), 6.74 (s, 2H), 3.58-3.55 (m, 4H), 2.40-2.37 (m , 4H), 2.17 (s, 2H), 2.10 (s, 6H),
1.06 (s, 9H). 1.06 (s, 9H).
实施例十九  Example 19
N- (2， 6-二甲基 -4- ( 1， 2， 3， 4-四氢喹啉 -2-基） -3， 3-二甲基丁酰胺盐酸盐的制备
Figure imgf000043_0002
Preparation of N-(2,6-Dimethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000043_0002
N- (2， 6-二甲基 -4- (2-喹啉基） 苯基） -3， 3-二甲基丁酰胺 （化合物 19A)  N-(2,6-Dimethyl-4-(2-quinolinyl)phenyl)-3,3-dimethylbutanamide (Compound 19A)
将 2-溴喹啉（209 mg， 1.00 mmol)溶于 5 ml 乙二醇二甲醚和 5 mL水的混合溶液中， 依 次加入 （4- (3， 3-二甲基丁酰胺基） -3， 5-二甲基苯基） 硼酸 （381 mg， 1.10 mmol) ， 双三 苯基磷二氯化钯 ( PdCl2(PPh3)2， 35 mg, 0.05 mmol) 和碳酸钾 ( 1.38 g， 10 mmol) 。 反应液在 氮气保护下 80°C搅拌 2小时， 分出乙二醇二甲醚层， 旋除乙二醇二甲醚， 粗品用石油醚 /乙酸 乙酯 =1 :1过柱纯化得到化合物 19A为白色固体 （380 mg， 100%收率） 。 MS: 347.2 (M+H+). 2-bromoquinoline (209 mg, 1.00 mmol) was dissolved in a mixed solution of 5 ml of ethylene glycol dimethyl ether and 5 mL of water, and (4-(3,3-dimethylbutyrylamide)- 3, 5-Dimethylphenyl)boronic acid (381 mg, 1.10 mmol), bistriphenylphosphine palladium dichloride (PdCl 2 (PPh 3 ) 2 , 35 mg, 0.05 mmol) and potassium carbonate ( 1.38 g, 10 mmol). The reaction solution was stirred under a nitrogen atmosphere at 80 ° C for 2 hours, and the ethylene glycol dimethyl ether layer was separated, and the ethylene glycol dimethyl ether was spun off. The crude product was purified by petroleum ether / ethyl acetate = 1 : 1 to obtain compound 19A. As a white solid (380 mg, 100% yield). MS: 347.2 (M+H + ).
N- (2， 6-二甲基 -4- ( 1， 2， 3， 4-四氢喹啉 -2-基） -3， 3-二甲基丁酰胺盐酸盐 （化合物 N-(2,6-Dimethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)-3,3-dimethylbutanamide hydrochloride (compound)
19) 19)
本品由化合物 19A按照化合物 15的制备方法合成， 56%收率。 MS: 351.3 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 9.17 (s, 1H), 7.13 (s, 2H), 7.02 (brs, 2H), 6.70-6.82 (brs, 2H), 4.39 (brs, 1H), 2.84-2.89 (m， 2H), 2.22 (s， 2H), 2.16 (s， 6H)， 1.95-2.05 (brs, 2H), 1.07 (s， 9H). This product was synthesized from the compound 19A according to the preparation method of the compound 15 in 56% yield. MS: 351.3 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 9.17 (s, 1H), 7.13 (s, 2H), 7.02 (brs, 2H), 6.70-6.82 (brs, 2H) ), 4.39 (brs, 1H), 2.84-2.89 (m, 2H), 2.22 (s, 2H), 2.16 (s, 6H), 1.95-2.05 (brs, 2H), 1.07 (s, 9H).
实施例二十  Example twenty
N-(4-(6-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺盐酸盐的制 备
Figure imgf000044_0001
 N- (4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide hydrochloride Preparation of salt
Figure imgf000044_0001
N-(4-氟苯基)肉桂酰胺 （化合物 20A)  N-(4-fluorophenyl)cinnamamide (Compound 20A)
将吡啶（ 1.46 mL)和 4-二甲胺基吡啶溶于 10 mL 的二氯甲烷中， 降温至 0°C， 氮气保护 下， 滴加肉桂酰氯 （3.00 g， 0.018 mol) 的二氯甲烷溶液 10 mL， 搅拌 15分钟后， 0°C下滴加 4-氟苯胺 （2.00 g， 0.018 mol) 的二氯甲烷溶液 10 mL， 10分钟后滴加完毕， 搅拌 15分钟。 升 至室温， 搅拌 4个小时。 反应完毕， 加入水， 用二氯甲烷萃取三遍， 合并二氯甲烷层， 干燥， 粗品经石油醚 /乙酸乙酯 =1 : 1过柱纯化得化合物 20A为白色固体 (4.30 g， 99%收率）。 MS: 242.1 (M+H+).  Dissolve pyridine ( 1.46 mL) and 4-dimethylaminopyridine in 10 mL of dichloromethane, cool to 0 ° C, and add cinnamoyl chloride (3.00 g, 0.018 mol) in dichloromethane under nitrogen. 10 mL, after stirring for 15 minutes, 10 mL of a solution of 4-fluoroaniline (2.00 g, 0.018 mol) in dichloromethane was added dropwise at 0 ° C, and after 10 minutes, the dropwise addition was completed, and the mixture was stirred for 15 minutes. Bring to room temperature and stir for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with dichloromethane, and the mixture was combined with methylene chloride. The methylene chloride layer was evaporated to dryness, and the crude product was purified by petroleum ether / ethyl acetate = 1 : 1 to obtain compound 20A as white solid (4.30 g, 99%. rate). MS: 242.1 (M+H+).
6-氟喹啉 -2-醇 （化合物 20B)  6-fluoroquinolin-2-ol (compound 20B)
将化合物 20A ( 3.93 g, 0.016 mol) 与三氯化铝 （6.52 g， 0.049 mol) 置于封管中， 快速升 温至三氯化铝的熔融状， 并于 120°C下搅拌反应 3小时。 冷却至室温， 加入冰水， 乙酸乙酯 萃取三遍， 合并有机层， 干燥， 粗品用石油醚 /乙酸乙酯 =1 :5过柱纯化得到化合物 20B为灰色 固体 （1.74 g，66%收率） 。 MS: 164.2 (M+H+).  Compound 20A (3.93 g, 0.016 mol) and aluminum trichloride (6.52 g, 0.049 mol) were placed in a sealed tube, rapidly heated to a molten aluminum trichloride, and stirred at 120 ° C for 3 hours. After cooling to room temperature, ice water was added, and ethyl acetate was evaporated and evaporated, evaporated, evaporated, evaporated, ). MS: 164.2 (M+H+).
2-氯 -6-氟喹啉 （化合物 20C)  2-chloro-6-fluoroquinoline (Compound 20C)
本品由化合物 1A和苯基膦酰二氯按照化合物 1A的制备方法合成， 75%收率。 MS: 182.1(M+H+). This product was synthesized from Compound 1A and phenylphosphonic dichloride according to the preparation method of Compound 1A in 75% yield. MS: 182.1 (M+H + ).
N-(4-(6-氟喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合物 20D)  N-(4-(6-fluoroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 20D)
将化合物 20C (227 mg， 1.25 mmol)溶于 15 mL 乙二醇二甲醚和 15 mL水的混合溶液中， 依次向溶液中加入 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 -2-基）苯基) -3 , 3-二甲基丁酰胺 （476 mg， 1.38 mmol) ， 碳酸钾 （4.15 g， 30 mmol) ， 双三苯基磷二氯化 钯 ( 88 mg, 0.13 mmol) 。 氮气保护下， 反应液 80°C搅拌 3个小时， 反应完毕， 分出有机层， 旋干， 粗品用石油醚 /乙酸乙酯 =1 : 1过柱纯化得到目标化合物， 为白色固体（258 mg，57% 收 率） 。 MS: 365.2 (M+H+).  Compound 20C (227 mg, 1.25 mmol) was dissolved in a mixture of 15 mL of ethylene glycol dimethyl ether and 15 mL of water, and N-(2,6-dimethyl-4-(4,4,4, 4, 5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,3-dimethylbutanamide (476 mg, 1.38 mmol), potassium carbonate ( 4.15 g, 30 mmol), bistriphenylphosphine palladium dichloride (88 mg, 0.13 mmol). Under a nitrogen atmosphere, the reaction mixture was stirred at 80 ° C for 3 hours. After completion of the reaction, the organic layer was separated, dried, and then purified eluted with petroleum ether / ethyl acetate = 1 : 1 to give the title compound as white solid (258 mg , 57% yield). MS: 365.2 (M+H+).
N-(4-(6-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺盐酸盐 （化 合物 20) 本品由化合物 20D 按照化合物 15的制备方法合成， 45%收率。 MS: 369.3 (Μ+Η+) Η NMR (400 MHz, DMSO- 6) δ: 9.19 (s， 1H), 7.17 (s， 1H), 6.91-6.96 (brs, 3H), 4.37-4.39 (m， 1H)， 2.90-2.92 (m， 1H), 2.76-2.77 (m， 1H), 2.23 (s， 2H), 2.16 (s， 6H)， 2.00-2.08 (brs, 2H), 1.07 (s， 9H). 实施例二 ^一 N- (4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide hydrochloride Salt (compound 20) This product was synthesized from Compound 20D according to the preparation method of Compound 15, 45% yield. MS: 369.3 (Μ+Η + ) Η NMR (400 MHz, DMSO-6) δ: 9.19 (s, 1H), 7.17 (s, 1H), 6.91-6.96 (brs, 3H), 4.37-4.39 (m, 1H), 2.90-2.92 (m, 1H), 2.76-2.77 (m, 1H), 2.23 (s, 2H), 2.16 (s, 6H), 2.00-2.08 (brs, 2H), 1.07 (s, 9H) Example 2
N-(4-(8-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺的制备 Preparation of N- (4-(8-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000045_0001
Figure imgf000045_0001
N-(2-氟苯基)肉桂酰胺 （化合物 21A)  N-(2-fluorophenyl)cinnamamide (Compound 21A)
本品由 2-氟苯胺和肉桂酰氯按照化合物 20A的制备方法合成， 93%收率。  This product was synthesized from 2-fluoroaniline and cinnamoyl chloride according to the preparation method of Compound 20A, 93% yield.
8-氟喹啉 -2-醇 （化合物 21B)  8-fluoroquinolin-2-ol (Compound 21B)
本品由化合物 21A按照化合物 20B的制备方法合成， 75%收率。  This product was synthesized from Compound 21A according to the preparation method of Compound 20B in a yield of 75%.
2-氯 -8-氟喹啉 （化合物 21C)  2-chloro-8-fluoroquinoline (Compound 21C)
本品由化合物 28B按照化合物 1A的制备方法合成， 47%收率。  This product was synthesized from Compound 28B according to the preparation method of Compound 1A, 47% yield.
N-(4-(8-氟喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合物 21D)  N-(4-(8-fluoroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 21D)
本品由化合物 21C和 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 -2- 基） 苯基） -3， 3-二甲基丁酰胺按照化合物 20D的制备方法合成， 50% 收率。  This product consists of compound 21C and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 50% yield.
N-(4-(8-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺（化合物 21 ) 将化合物 21D (400 mg, 1.13 mmol)溶于 10 mL 的甲醇溶液中，加入二氧化铂（40 mg)， 滴加一滴醋酸， 氢气置换反应体系三遍， 室温搅拌反应过夜。 反应完毕， 滤除催化剂， 滤液 旋干， 粗品经制备分离得到化合物 21为白色固体 （360 mg，90%收率） 。 MS: 369.3 (M+H+)。 1H NMR (400 MHz, DMSO- 6) δ: 9.10 (s, 1H)， 7.01 (s, 2H), 6.86 (m， 1H)， 6.74 (d, J= 9.6 Hz, 1H), 6.45 (m， 1H), 5.78 (s, 1H), 4.39 (m， 1H), 2.77(m, 1H), 2.55 (m， 1H), 2.21 (s, 2H), 2.13 (s, 6H)， 1.88 (m, 2H), 1.06 (s， 9H). N- (4-(8-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (compound) 21) Compound 21D (400 mg, 1.13 mmol) was dissolved in 10 mL of methanol solution, platinum dioxide (40 mg) was added, and a drop of acetic acid was added dropwise. The reaction system was replaced with hydrogen three times, and the reaction was stirred at room temperature overnight. After completion of the reaction, the catalyst was filtered off, the filtrate was evaporated to dryness, and the crude product was isolated to afford compound 21 as a white solid (360 mg, 90% yield). MS: 369.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.10 (s, 1H), 7.01 (s, 2H), 6.86 (m, 1H), 6.74 (d, J = 9.6 Hz, 1H), 6.45 (m, 1H) ), 5.78 (s, 1H), 4.39 (m, 1H), 2.77 (m, 1H), 2.55 (m, 1H), 2.21 (s, 2H), 2.13 (s, 6H), 1.88 (m, 2H) , 1.06 (s, 9H).
实施例二十二  Example twenty two
N-(4-(6，8-二氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺的制备
Figure imgf000046_0001
N-(4-(6,8-Difluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Preparation of amide
Figure imgf000046_0001
N-(2，4-二氟苯基)肉桂酰胺 （化合物 22A)  N-(2,4-difluorophenyl)cinnamamide (Compound 22A)
本品由 2，4-二氟苯胺和肉桂酰氯按照化合物 20A的制备方法合成， 98%收率。 MS: 260.1 (M+H+).  This product was synthesized from 2,4-difluoroaniline and cinnamoyl chloride according to the preparation method of Compound 20A, 98% yield. MS: 260.1 (M+H+).
6，8-二氟喹啉 -2-醇 （化合物 22B)  6,8-difluoroquinolin-2-ol (compound 22B)
本品由化合物 22A按照化合物 20B的制备方法合成， 66%收率。 MS: 182.1 CM+H+)。 2-氯 -6， 8-二氟喹啉 （化合物 22C) This product was synthesized from Compound 22A according to the preparation method of Compound 20B, yield 66%. MS: 182.1 CM+H + ). 2-chloro-6, 8-difluoroquinoline (Compound 22C)
本品由化合物 22B和苯基膦酰二氯按照化合物 1A的制备方法合成， 78%收率。 MS: 200.0 (M+H+).  This product was synthesized from Compound 22B and phenylphosphonic dichloride according to the preparation method of Compound 1A, with a yield of 78%. MS: 200.0 (M+H+).
N-(4-(6，8-二氟喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合物 22D)  N-(4-(6,8-Difluoroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 22D)
本品由化合物 22C和 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 -2- 基)苯基) -3，3-二甲基丁酰胺按照化合物 20D的制备方法合成， 100% 收率。 MS: 383.3(M+H+). This product consists of compound 22C and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 100% yield. MS: 383.3 (M+H + ).
N-(4-(6，8-二氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺 （化合 物 22)  N-(4-(6,8-Difluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide (compound 22)
本品由化合物 22D按照化合物 21的制备方法合成， 61%收率。 MS: 387.3 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 9.10 (s， 1H), 7.02 (s， 2H), 6.89-6.94 (m， 1H), 6.69 (d， J= 9.6Hz， 1H)， 5.68 (s， 1H)， 4.34-4.36 (m， 1H)， 2.76-2.83(m, 1H)， 2.54-2.60 (m， 1H)， 2.21 (s， 2H), 2.21(s, 6H)， 1.84-2.00(m, 2H), 1.06 (s， 9H). This product was synthesized from Compound 22D according to the preparation method of Compound 21, 61% yield. MS: 387.3 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 9.10 (s, 1H), 7.02 (s, 2H), 6.89-6.94 (m, 1H), 6.69 (d, J = 9.6Hz, 1H), 5.68 (s, 1H), 4.34-4.36 (m, 1H), 2.76-2.83 (m, 1H), 2.54-2.60 (m, 1H), 2.21 (s, 2H), 2.21 ( s, 6H), 1.84-2.00(m, 2H), 1.06 (s, 9H).
实施例二十三  Example twenty-three
N-(2，6-二甲基 -4- ( 1-甲基-1， 2， 3， 4-四氢喹啉 -2-基） 苯基) -3， 3-二甲基丁酰胺盐酸盐 的制备
Figure imgf000046_0002
N-(2,6-Dimethyl-4-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)-3,3-dimethylbutyramide Preparation of acid salt
Figure imgf000046_0002
N- (2， 6-二甲基 -4- (2-喹啉基） 苯基） -3， 3-二甲基丁酰胺 （化合物 23A)  N-(2,6-Dimethyl-4-(2-quinolinyl)phenyl)-3,3-dimethylbutanamide (Compound 23A)
本品由 2-溴喹啉和 （4- (3， 3-二甲基丁酰胺基） -3， 5-二甲苯基） 硼酸按照化合物 19A 的制备方法合成， 85%收率。 MS: 347.2 (M+H+). N- (2， 6-二甲基 -4- ( 1， 2， 3， 4-四氢喹啉 -2-基） -3， 3-二甲基丁酰胺 （化合物 23B) 本品由化合物 23A按照化合物 21的制备方法合成， 62%收率。 MS: 351.3 (M+H+). This product was synthesized from 2-bromoquinoline and (4-(3,3-dimethylbutyramido)-3,5-dimethylphenyl)boronic acid according to the preparation method of compound 19A in 85% yield. MS: 347.2 (M+H + ). N-(2,6-Dimethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)-3,3-dimethylbutanamide (Compound 23B) This product is compound 23A Synthesized according to the preparation method of Compound 21, 62% yield. MS: 351.3 (M+H + ).
N-(2，6-二甲基 -4- ( 1-甲基-1， 2， 3， 4-四氢喹啉 -2-基） 苯基) -3， 3-二甲基丁酰胺盐酸盐 (化合物 23 ) 将化合物 23B ( 152 mg， 0.43 mmol)溶于 10 mL 甲醇中，依次加入 0.1 mL的甲醛水溶液， 氰基硼氢化钠（ 54 mg， 0.86 mmol)和 1滴醋酸。 反应液于 60°C下搅拌 3小时。 反应完， 用水 淬灭， 旋除甲醇， 剩余水相用乙酸乙酯萃取三遍， 干燥， 旋除溶液得粗品， 经制备分离得产 物， 该产物用盐酸***溶液酸化得其盐酸盐即为化合物 23， 白色固体 （132 mg，76%收率） 。 MS: 365.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.06 (s， 1H), 7.04-7.08 (t， Ji = 1.2Hz, J2 = 7.2Hz 1H), 6.91 (d, J= 7.2 Hz, 1H), 6.82 (s， 2H), 6.63 (d， J= 8.8Hz， 1H), 6.51-6.55 (t， Ji = 6.8 Hz, J2 = 8.0 Hz 1H), 4.43-4.46 (t， Ji = J2 = 4.8Hz， 1H), 2.79 (s， 3H), 2.51-2.61 (m， 1H), 2.39-2.47 (m， 1H), 2.20 (s， 2H), 2.10 (s， 6H)， 1.89-2.08 (m， 2H), 1.06 (s， 9H). N-(2,6-Dimethyl-4-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)-3,3-dimethylbutyramide Acid salt (Compound 23) Compound 23B (152 mg, 0.43 mmol) was dissolved in 10 mL methanol, and then 0.1 mL aqueous sodium hydroxide, sodium cyanoborohydride (54 mg, 0.86 mmol) and 1 drop of acetic acid. The reaction solution was stirred at 60 ° C for 3 hours. After the reaction is completed, it is quenched with water, and the methanol is evaporated. The residual aqueous phase is extracted with ethyl acetate three times, dried, and the solution is evaporated to give a crude product. The product is isolated and acidified to give the hydrochloride salt. Compound 23, white solid (132 mg, 76% yield). MS: 365.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.06 (s, 1H), 7.04-7.08 (t, Ji = 1.2 Hz, J 2 = 7.2 Hz 1H), 6.91 (d , J= 7.2 Hz, 1H), 6.82 (s, 2H), 6.63 (d, J= 8.8Hz, 1H), 6.51-6.55 (t, Ji = 6.8 Hz, J 2 = 8.0 Hz 1H), 4.43-4.46 (t, Ji = J 2 = 4.8Hz, 1H), 2.79 (s, 3H), 2.51-2.61 (m, 1H), 2.39-2.47 (m, 1H), 2.20 (s, 2H), 2.10 (s, 6H), 1.89-2.08 (m, 2H), 1.06 (s, 9H).
实施例二十四  Example twenty four
N-(4-(6-氟小甲基 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合 物 24) 的制备
Figure imgf000047_0001
N-(4-(6-Fluoromethyl-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide Preparation of compound 24)
Figure imgf000047_0001
化合物 20 ( 143 mg， 0.37 mmol)溶于 10 mL 甲醇溶液，搅拌下，依次加入甲醛水溶液（0.3 mL) ， 氰基硼氢化钠 （47 mg， 0.74 mmol) 和一滴醋酸。 反应液回流搅拌过夜。 加入水， 用 乙酸乙酯萃取三遍， 合并有机层， 干燥， 旋干， 粗品经制备分离得化合物 24 ( 117 mg, 83% 收率） 。 MS: 381 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.06 (s， 1Η), 6.86-6.92 (m， 1H)， 6.79-6.82 (m 3H), 6.58-6.62 (dd， Ji = J2 = 4.8Hz， 1H), 4.41 (t， Ji = 5.2Hz, J2 = 4.4Hz， 1H), 2.76 (s， 3H), 2.59-2.63 (m， 1H), 2.44-2.50 (m， 1H), 2.20 (s， 2H), 2.10 (s， 6H), 1.91-2.04 (m， 2H), 1.06 (s， 9H). Compound 20 (143 mg, 0.37 mmol) was dissolved in 10 mL of MeOH. EtOAc (EtOAc) (EtOAc) The reaction was stirred at reflux overnight. Water was added, and the mixture was extracted three times with ethyl acetate. EtOAc was evaporated. MS: 381 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.06 (s, 1 Η), 6.86-6.92 (m, 1H), 6.79-6.82 (m 3H), 6.58-6.62 (dd , Ji = J 2 = 4.8Hz, 1H), 4.41 (t, Ji = 5.2Hz, J 2 = 4.4Hz, 1H), 2.76 (s, 3H), 2.59-2.63 (m, 1H), 2.44-2.50 ( m, 1H), 2.20 (s, 2H), 2.10 (s, 6H), 1.91-2.04 (m, 2H), 1.06 (s, 9H).
实施例二十五  Example twenty five
N-(4-(6，8-二氟小甲基 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺（化 合物 25 ) 的制备
Figure imgf000047_0002
本品由化合物 22按照化合物 24的制备方法合成， 74%收率。 MS: 401 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.07 (s， 1H), 6.95-7.01 (m， 3H), 6.74-6.76(m, 1H), 4.07-4.1 l(dd, Ji = 3.6Hz, J2 = 4.0Hz, 1H)， 2.75-2.84 (m， 1H)， 2.74 (s, 3H), 2.51-2.60 (m， 1H)， 2.21(s, 2H), 2.13 (s, 6H)， 2.08 (s， 1H), 1.73-1.83 (m， 1H), 1.06 (s， 9H). N-(4-(6,8-Difluorosuccinyl-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethyl Preparation of butanamide (compound 25)
Figure imgf000047_0002
This product was synthesized from Compound 22 according to the preparation method of Compound 24, 74% yield. MS: 401 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.07 (s, 1H), 6.95-7.01 (m, 3H), 6.74-6.76 (m, 1H), 4.07-4.1 l(dd, Ji = 3.6Hz, J 2 = 4.0Hz, 1H), 2.75-2.84 (m, 1H), 2.74 (s, 3H), 2.51-2.60 (m, 1H), 2.21(s, 2H), 2.13 (s, 6H), 2.08 (s, 1H), 1.73-1.83 (m, 1H), 1.06 (s, 9H).
实施例二十六  Example twenty six
N- ( 4- ( 1， 2， 3， 4-四氢异喹啉 -3-基） 2， 6-二甲基苯） -3， 3-二甲基丁酰胺的制备  Preparation of N-(4-(1,2,3,4-tetrahydroisoquinolin-3-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000048_0001
Figure imgf000048_0001
N- ( 4 (-异喹啉 -3-基） 2， 6-二甲基苯） -3， 3-二甲基丁酰胺 （化合物 26A)  N-( 4 (-Isoquinolin-3-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 26A)
本品由 3-溴喹啉和 N- ( 2， 6-二甲基 -4- ( 4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 -2-基） 苯基） -3， 3-二甲基丁酰胺按照化合物 20D的制备方法合成， 91%收率。  This product consists of 3-bromoquinoline and N-( 2, 6-dimethyl-4-( 4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl)-3,3-dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 91% yield.
N- ( 4- ( 1， 2， 3， 4-四氢异喹啉 -3-基） 2， 6-二甲基苯） -3， 3-二甲基丁酰胺（化合物 26 ) 本品由化合物 26A按照化合物 21的制备方法合成， 25% 收率。 MS: 350.8 (M+H+). 1HN-(4-(1,2,3,4-tetrahydroisoquinolin-3-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 26) Compound 26A was synthesized according to the method for the preparation of compound 21 in 25% yield. MS: 350.8 (M+H + ). 1H
NMR (400 MHz, DMSO- 6) δ: 9.1 1 (s, 1H), 7.10 (m， 6H)， 4.02 (m， 2H), 3.80 (m， 1H), 3.36 (m，NMR (400 MHz, DMSO-6) δ: 9.1 1 (s, 1H), 7.10 (m, 6H), 4.02 (m, 2H), 3.80 (m, 1H), 3.36 (m,
1H), 2.86 (m， 1H), 2.75 (m， 1H), 2.22 (s， 2H), 2.15 (s， 6H)， 1.07 (s， 9H). 1H), 2.86 (m, 1H), 2.75 (m, 1H), 2.22 (s, 2H), 2.15 (s, 6H), 1.07 (s, 9H).
实施例二十七  Example twenty seven
N-(2，6-二甲 -4- ( 1， 2， 3， 4-四氢喹啉 -3-基) 苯基) -3， 3-二甲基丁酰胺盐酸盐的制备
Figure imgf000048_0002
Preparation of N-(2,6-dimethyl-4-(1,2,3,4-tetrahydroquinolin-3-yl)phenyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000048_0002
N- ( 2， 6-二甲基 -4- ( 3-喹啉基） 苯基） -3， 3-二甲基丁酰胺 （化合物 27A)  N-( 2, 6-Dimethyl-4-(3-quinolinyl)phenyl)-3,3-dimethylbutanamide (Compound 27A)
本品由 3-喹啉硼酸和 N- ( 4-溴 -2， 6-二甲苯基） -3， 3-二甲基丁酰胺按照化合物 19A的 制备方法合成， 82%收率。 MS: 347.2 (M+H+). This product is synthesized from 3-quinoline boronic acid and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 19A, 82% yield. MS: 347.2 (M+H + ).
N-(2，6-二甲基 -4- ( 1， 2， 3， 4-四氢喹啉 -3-基）苯基) -3， 3-二甲基丁酰胺盐酸盐（化合物 N-(2,6-Dimethyl-4-(1,2,3,4-tetrahydroquinolin-3-yl)phenyl)-3,3-dimethylbutanamide hydrochloride (compound)
27 ) 化合物 27A ( 443 mg, 1.28 mmol) 溶于 20 mL 的甲苯溶液中， 加入 2,6-二甲基 -1 ,4-二氢 -3,5-吡啶二羧酸二乙酯 ( 777 mg, 3.07 mmol) 和磷酸二苯酯 ( 32 mg, 0.13 mmol ) 。 氮气保护 下， 加热至 120°C搅拌过夜。 反应液用饱和氯化钠水洗， 旋除甲苯， 粗品经制备得产物， 该 产物用盐酸***溶液酸化得到化合物 27为白色固体 (224 mg, 45% 收率)。 MS: 351.3 (M+H+). Ή NMR (400 MHz, DMSO-d6) δ: 9.16 (s， 1H), 7.19-7.22 (m， 2H), 3.34-3.49 (m， 2H), 3.11-3.15 (m, 1H), 2.98-3.00 (m, 2H), 2.22 (s, 2H), 2.16 (s, 6H)， 1.07 (s, 9H). 27) Compound 27A (443 mg, 1.28 mmol) was dissolved in 20 mL of toluene and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (777 mg) , 3.07 mmol) and diphenyl phosphate (32 mg, 0.13 mmol). Heat under nitrogen to heat to 120 ° C and stir overnight. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. MS: 351.3 (M+H + ). NMR NMR (400 MHz, DMSO-d6) δ: 9.16 (s, 1H), 7.19-7.22 (m, 2H), 3.34-3.49 (m, 2H), 3.11-3.15 (m, 1H), 2.98-3.00 ( m, 2H), 2.22 (s, 2H), 2.16 (s, 6H), 1.07 (s, 9H).
实施例二十八  Example twenty eight
N-(4-(3，4-二氢喹啉 -1(2H)-基) -2，6-二甲基 )-3， 3-二甲基丁酰胺的制备
Figure imgf000049_0001
Preparation of N-(4-(3,4-dihydroquinolin-1(2H)-yl)-2,6-dimethyl)-3,3-dimethylbutanamide
Figure imgf000049_0001
本品由四氢喹啉和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的制备 方法合成， 收率 34%。 MS: 351 (M+H+). 1HNMR (DMSO, 400 MHz): δ 9.07 (s， 1Η), 6.98 (d, J = 7.2 Hz, 1H), 6.91 (s， 2H), 6.84-6.89 (m，lH)， 6.58-6.64 (m， 1H), 6.55 (d， J= 8 Hz, 1H), 3.53 (t， J = 5.6 Hz, 2H), 2.76 (t, J= 6.4 Hz, 2H), 2.21 (s， 2H), 2.11 (s， 6H)， 1.89-1.96 (m， 2H), 1.06 (s， 9H). 实施例二十九  This product was synthesized from tetrahydroquinoline and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 5 in a yield of 34%. MS: 351 (M+H+). 1H NMR (DMSO, 400 MHz): δ 9.07 (s, 1 Η), 6.98 (d, J = 7.2 Hz, 1H), 6.91 (s, 2H), 6.84-6.89 (m, lH), 6.58-6.64 (m, 1H), 6.55 (d, J= 8 Hz, 1H), 3.53 (t, J = 5.6 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.21 ( s, 2H), 2.11 (s, 6H), 1.89-1.96 (m, 2H), 1.06 (s, 9H). Example twenty-nine
N-(4- (吲哚 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺的盐酸盐的制备
Figure imgf000049_0002
Preparation of hydrochloride salt of N-(4-(indol-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000049_0002
叔丁基 -2- (4- (3， 3-二甲基丁酰胺基） 3， 5-二甲苯基） -1H-吲哚 -1-羧酸酯（化合物 29A) 本品由 ( 1- (叔丁基丁酰胺基) -1H-吲哚 -2-基)硼酸和 N- (4-溴 -2， 6-二甲苯基) -3， 3- 二甲基丁酰胺按照化合物 19A的制备方法合成， 59%收率。 MS: 379.3 (M-56+H+). tert-Butyl-2-(4-(3,3-dimethylbutyryl) 3,5-dimethylphenyl)-1H-indole-1-carboxylate (Compound 29A) Preparation of (tert-butylbutyrylamide)-1H-indol-2-yl)boronic acid and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to compound 19A Method synthesis, 59% yield. MS: 379.3 (M-56+H + ).
叔丁基 -2- (4- (3， 3-二甲基丁酰胺） 3， 5-二甲苯基） 吲哚 -1-羧酸酯 （化合物 29B) 将化合物 29A (200 mg， 0.46 mmol) 溶于 5 mL 的甲醇溶液中， 加入 10%的钯碳催化剂 (40 mg) ， 氢气置换三次， 加热至 45°C搅拌反应 2小时， 滤除催化剂， 旋除甲醇得到化 合物 29B的粗品， 直接用于下一步反应 （238 mg， 100%收率） 。 MS: 381.2 (M+H+). tert-Butyl-2-(4-(3,3-dimethylbutyramide) 3,5-dimethylphenyl)indole-1-carboxylate (Compound 29B) Compound 29A (200 mg, 0.46 mmol) Dissolve in 5 mL of methanol solution, add 10% palladium carbon catalyst (40 mg), replace with hydrogen three times, heat to 45 ° C and stir the reaction for 2 hours, filter off the catalyst, spin off the methanol to obtain the crude product of compound 29B, directly In the next step (238 mg, 100% yield). MS: 381.2 (M+H + ).
N-(4- (吲哚 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺盐酸盐 （化合物 29)  N-(4-(indol-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide hydrochloride (Compound 29)
将化合物 29B (238 mg, 0.55 mmol) 溶于 6 mL 的二氯甲烷溶液中， 滴加 1 mL 的三氟 乙酸， 室温下搅拌反应 3小时， 旋干二氯甲烷和三氟乙酸， 剩余物用 50 mL饱和的碳酸 氢钠水溶液溶解， 乙酸乙酯萃取三遍， 干燥， 旋除乙酸乙酯， 粗品经制备分离得产物， 再用盐酸***溶液酸化得其盐酸盐即为化合物 29， 为白色固体 （150 mg，74%收率） 。 MS: 337.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 7.36-7.55 (m， 4Η)， 7.26 (s, 2Η), 5.24-5.29 (t, Ji = 8.4Hz， h = 8.8Hz, 1H), 3.67-3.73 (m， 1H), 3.52-3.58 (m， 1H), 2.35 (s， 2H), 2.28 (s， 6H)， 1.16 (s， 9H). 实施例三十 Compound 29B (238 mg, 0.55 mmol) was dissolved in 6 mL of dichloromethane, 1 mL of trifluoroacetic acid was added dropwise, and the reaction was stirred at room temperature for 3 hours, and then dichloromethane and trifluoroacetic acid were evaporated. Dissolve in 50 mL of a saturated aqueous solution of sodium hydrogencarbonate, extract three times with ethyl acetate, dry, and then remove ethyl acetate. The crude product is isolated to obtain the product, which is acidified to give the compound as a compound. Solid (150 mg, 74% yield). MS: 337.3 (M+H+). 1H NMR (400 MHz, CD 3 OD) δ: 7.36-7.55 (m, 4 Η), 7.26 (s, 2 Η), 5.24-5.29 (t, Ji = 8.4 Hz, h = 8.8 Hz, 1H), 3.67-3.73 (m, 1H), 3.52-3.58 (m, 1H), 2.35 (s, 2H), 2.28 (s, 6H), 1.16 (s, 9H). Example thirty
N- (4- (吲哚小基) -2， 6-二甲基) -3， 3-二甲基丁酰胺 (化合物 30) 的制备
Figure imgf000050_0001
Preparation of N-(4-(indolyl)-2,6-dimethyl)-3,3-dimethylbutanamide (Compound 30)
Figure imgf000050_0001
本品由二氢吲哚和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的制备 方法合成， 收率 34%。 MS: 337 (M+H+). ^MR (CDC13, 400 MHz): δ 7.04-7.17 (m， 3H), 6.95 (s: 2H), 6.75 (t， J= 7.2 Hz, 1H)， 6.57 (s，lH)， 3.92 (t， J= 8.4 Hz, 2H), 3.11 (t, J= 8.8 Hz, 2H), 2.29 (s， 2H), 2.24 (s, 6H)， 1.16 (s, 9H). This product was synthesized from indoline and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 5, yield 34%. MS: 337 (M+H+). ^MR (CDC1 3 , 400 MHz): δ 7.04-7.17 (m, 3H), 6.95 (s : 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.57 ( s,lH), 3.92 (t, J= 8.4 Hz, 2H), 3.11 (t, J= 8.8 Hz, 2H), 2.29 (s, 2H), 2.24 (s, 6H), 1.16 (s, 9H).
实施例三 ^一  Embodiment 3 ^1
N-(4- (6-氟 -1，2，3，4-四氢萘 -2-基） 2，6-二甲基苯) -3，3-二甲基丁酰胺的制备
Figure imgf000050_0002
Preparation of N-(4-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000050_0002
2-三氟甲磺酰氧基 -6-氟 -1,4-二氢萘 （化合物 31A)  2-Trifluoromethanesulfonyloxy-6-fluoro-1,4-dihydronaphthalene (Compound 31A)
于 -78°C下，往 LiHMDS (双三甲基硅基胺基锂， 1M, 14.6 mL, 14.6 mmol)的四氢呋喃（20 mL) 溶液中滴加 6-氟 -3,4-二氢萘 -2 ( 1H) -酮 （2 g， 12.2 mmol) 的四氢呋喃 （20 mL) 溶液， 反应一小时后， 滴加 N-苯基双 (三氟甲烷磺酰)亚胺 （4.8 g， 13.4 mmol) 的四氢呋喃 （20 mL) 溶液， 于 -78°C下继续搅拌一小时， 然后升至室温下搅拌 15小时。 用饱和碳酸氢钠溶液淬灭 反应， 加入 2M的氢氧化钠溶液， 用乙酸乙酯 G x lOO mL)萃取， 饱和食盐水洗， 无水硫酸 钠干燥， 旋干得粗品， 用石油醚纯化得化合物 31A ( l g, 28% 收率） 。  To a solution of LiHMDS (bis-trimethylsilylamide lithium, 1M, 14.6 mL, 14.6 mmol) in tetrahydrofuran (20 mL) at -78 ° C, 6-fluoro-3,4-dihydronaphthalene was added dropwise. 2 ( 1H)-ketone (2 g, 12.2 mmol) in tetrahydrofuran (20 mL). After one hour, N-phenylbis(trifluoromethanesulfonyl)imide (4.8 g, 13.4 mmol) was added dropwise. A solution of tetrahydrofuran (20 mL) was stirred at -78 °C for one hour and then stirred at room temperature for 15 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, EtOAc (EtOAc) EtOAc. 31A ( lg, 28% yield).
N-(4- (6-氟 -1,4-二氢萘 -2-基） 2，6-二甲基苯) -3,3-二甲基丁酰胺 （化合物 31B)  N-(4-(6-fluoro-1,4-dihydronaphthalen-2-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 31B)
本品由化合物 31A和 N- (2,6-二甲基 -4- (4，4，5，5-四甲基 -1，3，2，-二氧杂硼烷 -2-基） 苯基） -3,3-二甲基丁酰胺按照化合物 20D的制备方法合成， 77% 收率。 MS: 366 (M+H+). This product consists of compound 31A and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)benzene -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 20D, 77% yield. MS: 366 (M+H + ).
N-(4- (6-氟 -1，2，3，4-四氢萘 -2-基） 2，6-二甲基苯) -3,3-二甲基丁酰胺 （化合物 31 ) 本品由化合物 31B按照化合物 29B的制备方法合成， 16% 收率。 MS: 368 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.06-7.03 (m, 1H), 7.00 (s, 2H), 6.84 (d, J= 14.8 Hz, 2H), 6.61 (s, 1H), 2.99-2.80 (m， 5H)， 2.33 (s， 2H), 2.27 (s， 6H)， 2.12-2.08 (m， 1H), 1.94-1.84 (m， 1H), 1.18 (s, 9H). 实施例三十二 N-(4-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 31) The product was synthesized from Compound 31B according to the method for the preparation of Compound 29B, 16% yield. MS: 368 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.06-7.03 (m, 1H), 7.00 (s, 2H), 6.84 (d, J = 14.8 Hz, 2H), 6.61 (s, 1H), 2.99-2.80 (m, 5H), 2.33 (s, 2H), 2.27 (s, 6H), 2.12-2.08 (m, 1H), 1.94-1.84 (m, 1H), 1.18 (s , 9H). Example thirty-two
N 2，6-二甲基 -4-(2，3，4，5-四氢 -1H-苯并 [6]氮杂卓 -1-基)苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000051_0001
N 2,6-Dimethyl-4-(2,3,4,5-tetrahydro-1H-benzo[6]azepin-1-yl)phenyl)-3,3-dimethylbutyl Preparation of amide
Figure imgf000051_0001
苯并环己酮肟 （化合物 32A)  Benzocyclohexanone oxime (Compound 32A)
本品由 1-四氢萘酮按照化合物 5C的制备方法合成， 收率 100%。  This product is synthesized from 1-tetralone according to the preparation method of compound 5C, and the yield is 100%.
4，5-二氢 -1H-苯并 [6]己内酰胺 -2(JH)-酮 （化合物 32B )  4,5-dihydro-1H-benzo[6]caprolactam-2(JH)-one (compound 32B)
化合物 32A (4.4 g， 27.3 mmol) 加入到多聚磷酸 （120 g) 中，升温至 80 °C 反应 16 小时， 将反应液加入到水 （50 mL) 中溶解， 乙酸乙酯萃取 （50 mLx3 ) ， 合并有机层干燥， 减压旋 干， 乙醇重结晶得到化合物 32B (3.8 g， 收率 84% )。  Compound 32A (4.4 g, 27.3 mmol) was added to polyphosphoric acid (120 g), and the mixture was warmed to 80 ° C for 16 hours. The reaction solution was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL×3) The combined organic layers were dried, dried under reduced pressure, and then evaporated to crystals to afford compound 32B (3.8 g, yield 84%).
2，3，4，5-四氢 -1H-苯并 [6]氮杂卓 （化合物 32C)  2,3,4,5-tetrahydro-1H-benzo[6]azepine (compound 32C)
本品由化合物 32B按照化合物 5G的制备方法合成， 收率 81%。  This product was synthesized from Compound 32B according to the preparation method of Compound 5G in a yield of 81%.
N 2，6-二甲基 -4-(2，3，4，5-四氢 -1H-苯并 [6]氮杂卓 -1-基)苯基) -3,3-二甲基丁酰胺 （化合物 N 2,6-Dimethyl-4-(2,3,4,5-tetrahydro-1H-benzo[6]azepin-1-yl)phenyl)-3,3-dimethylbutyl Amide
32) 32)
本品由化合物 32C和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的 制备方法合成，收率 27%。 MS: 365 (Μ+Η+). ^MR (DMSO, 400 ΜΗζ): δ 8.79 (s， 1H), 7.32-7.34 (m， 1H)， 7.22-7.27 (m， 1H)， 7.16-7.20 (m，lH)， 7.08-7.10 (m， 1H)， 6.23 (s, 2H), 3.57 (s, 2H), 2.57-2.60 (m, 2H), 2.15 (s, 2H), 1.99 (s, 6H), 1.73-1.75 (m, 2H), 1.60-1.61 (m, 2H), 1.04 (s, 9H). 实施例三十三  This product was synthesized from Compound 32C and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation of Compound 5 in a yield of 27%. MS: 365 (Μ+Η+). ^MR (DMSO, 400 ΜΗζ): δ 8.79 (s, 1H), 7.32-7.34 (m, 1H), 7.22-7.27 (m, 1H), 7.16-7.20 (m , lH), 7.08-7.10 (m, 1H), 6.23 (s, 2H), 3.57 (s, 2H), 2.57-2.60 (m, 2H), 2.15 (s, 2H), 1.99 (s, 6H), 1.73-1.75 (m, 2H), 1.60-1.61 (m, 2H), 1.04 (s, 9H). Example thirty-three
N-(4-(4，5-二氢 -IH-苯并 [J]氮杂卓 -3 H)-基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺的盐酸盐 的制备
Figure imgf000051_0002
N-(4-(4,5-Dihydro-IH-benzo[J]azepine-3 H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Preparation of amide hydrochloride
Figure imgf000051_0002
2，2'-(1，2-亚苯基)二乙醇 （化合物 33A)  2,2'-(1,2-phenylene)dipethanol (Compound 33A)
在圆底烧瓶中加入 LiAl¾ (氢化铝锂， 1.04 g， 30 mmol), THF (；四氢呋喃， 20.00 mL), 2,2'- (1,2-亚苯基)二乙酸 （2.00 g， 100 mmol)。反应液回流 16小时。 TLC 监测显示反应结束. 将 100 mL水滴加到反应液中， 过滤， 滤饼用乙酸乙酯洗涤。将有机层用无水硫酸钠干燥， 减压蒸出 有机溶剂得到化合物 33A的粗产品 (1.60 g， 收率 96%)。 无需纯化直接用于下一步反应。  Add LiAl3⁄4 (lithium aluminum hydride, 1.04 g, 30 mmol), THF (tetrahydrofuran, 20.00 mL), 2,2'- (1,2-phenylene) diacetic acid (2.00 g, 100 mmol). ). The reaction solution was refluxed for 16 hours. TLC monitoring showed the end of the reaction. 100 mL of water was added to the reaction mixture, filtered, and the filter cake was washed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (MgSO4). It was used directly in the next reaction without purification.
2，2'-(1，2-亚苯基)二 (-2,1-亚乙烯基)二甲磺酸酯 （化合物 33B)  2,2'-(1,2-phenylene)bis(-2,1-vinylidene)dimesylate (Compound 33B)
在圆底烧瓶中加入化合物 33A(498 mg， 3 mmol), 三乙胺 (606 mg， 6 mmol), 二氯甲烷 (10 mL 甲基磺酰氯 （684 mg， 6 mmol) 溶到 10 mL二氯甲烷当中， 缓慢滴加到反应液中。 室温 搅拌 30分钟。 TLC (EA:PE=1 :5)监测反应结束。 减压蒸出溶剂， 在瓶中加入 lOO mL乙酸乙 酯， 50mL水洗， 有机层用无水硫酸钠干燥， 过滤， 减压蒸出溶剂得到化合物 33B粗品 （1.00 g， 收率 100%)。 In a round bottom flask was added compound 33A (498 mg, 3 mmol), triethylamine (606 mg, 6 mmol), dichloromethane (10 mL methanesulfonyl chloride (684 mg, 6 mmol) dissolved in 10 mL of dichloro In methane, slowly add dropwise to the reaction solution. Stir for 30 minutes. TLC (EA: PE = 1:5) was monitored for the end of the reaction. The solvent was evaporated under reduced pressure, and ethyl acetate (100 mL) was evaporated, evaporated, evaporated, evaporated.
2，3，4，5-四氢 -1H-苯并 [ ]氮杂卓 （化合物 33C)  2,3,4,5-tetrahydro-1H-benzo[ ]azepine (compound 33C)
在封管中加入化合物 33B ( 644 mg, 2 mmol) ， 氨水 （；5 mL， 17%)于封管中 90 °C搅拌 3 小时。 LCMS检测反应结束。 减压蒸出溶剂得到化合物 33C (280 mg, 100% 收率）。 MS: 148 [Μ+Η]+. Compound 33B (644 mg, 2 mmol) and ammonia water (5 mL, 17%) were added to the sealed tube and stirred at 90 ° C for 3 hours. LCMS detected the end of the reaction. The solvent was evaporated under reduced pressure to give Compound 33C (280 mg, 100% yield). MS: 148 [Μ+Η] + .
Ν-(4-(4，5-二氢 -1H-苯并 [J]氮杂卓 -3 H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺盐酸盐 (化合物 33 )  Ν-(4-(4,5-Dihydro-1H-benzo[J]azepine-3 H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide hydrochloride (compound 33)
本品由化合物 33C和 N-(4-溴 -2,6-二甲基苯基) -3,3-二甲基丁酰胺按照化合物 7的制备方 法合成， 52%收率。 MS: 365 [M+H-HC1(36.5)]+. ^MR ( -DMSO, 400 MHz): δ 9.27 (s, 1H)， 7.22-7.15 (m, 4H), 3.65-2.96 (m, 8H), 2.22-2.10(m, 8H), 1.06(s, 9H). This product was synthesized from Compound 33C and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation of Compound 7. MS: 365 [M+H-HC1 (36.5)] + . ^MR (-DMSO, 400 MHz): δ 9.27 (s, 1H), 7.22-7.15 (m, 4H), 3.65-2.96 (m, 8H) , 2.22-2.10(m, 8H), 1.06(s, 9H).
实施例三十八  Example thirty eight
N-(6-(4，5-二氢噻吩并 [3，2-C]吡啶 -6(7H)-基) -2，4-二甲基吡啶 -3-基) -3，3-二甲基丁酰胺的制 备
Figure imgf000052_0001
N-(6-(4,5-Dihydrothieno[3,2- C ]pyridine-6(7H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Preparation of methylbutyric acid
Figure imgf000052_0001
6-(4，6-二甲基 -5-硝基吡啶 -2-基) -4，5，6，7-四氢噻吩并 [3，2-c]吡啶 （化合物 38A)  6-(4,6-Dimethyl-5-nitropyridin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Compound 38A)
本品由 4，5，6，7-四氢噻吩并 [3，2-C]吡啶和 6-氯 -2,4-二甲基 -3-硝基吡啶按照化合物 1B的制 备方法合成， 收率 79%。 This product is synthesized from 4,5,6,7-tetrahydrothieno[3,2- C ]pyridine and 6-chloro-2,4-dimethyl-3-nitropyridine according to the preparation method of compound 1B. The rate is 79%.
6-(4，5-二氢噻吩并 [3，2-c]吡啶 -6(7H)-基) -2,4-二甲基吡啶 -3-胺 （化合物 38B)  6-(4,5-Dihydrothieno[3,2-c]pyridine-6(7H)-yl)-2,4-dimethylpyridine-3-amine (Compound 38B)
本品由化合物 38A按照化合物 1C的制备方法合成， 收率 98%。  This product was synthesized from Compound 38A according to the preparation method of Compound 1C, yield 98%.
N-(6-(4，5-二氢噻吩并 [3，2-C]吡啶 -6(7H)-基) -2,4-二甲基吡啶 -3-基) -3,3-二甲基丁酰胺（化合 物 38 ) N-(6-(4,5-Dihydrothieno[3,2- C ]pyridine-6(7H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Methylbutyramide (compound 38)
本品由化合物 38B按照化合物 2的制备方法合成，收率 73%。 NMR (400 MHz, DMSO) δ: 7.26 (s, 1Η), 7.12 (d， J= 4.8 Hz, 2H), 6.85 (d， J= 4.8 Hz, 1H), 6.40 (s, 1H), 4.55 (s, 2H), 3.96 (t， J = 5.6 Hz, 2H), 2.94 (t， J = 5.6 Hz, 2H), 2.34 (s， 3H), 2.26 (s， 2H), 2.17 (s， 3H), 1.13 (s, 9H). MS: 358.5 [M+H]+. This product was synthesized from Compound 38B according to the preparation method of Compound 2, and the yield was 73%. NMR (400 MHz, DMSO) δ: 7.26 (s, 1 Η), 7.12 (d, J = 4.8 Hz, 2H), 6.85 (d, J = 4.8 Hz, 1H), 6.40 (s, 1H), 4.55 (s , 2H), 3.96 (t, J = 5.6 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 2H), 2.17 (s, 3H), 1.13 (s, 9H). MS: 358.5 [M+H] + .
实施例三十九 N-(6-(4，5-二氢噻吩并 [2，3-c]吡啶 -6(7H)-基) -2，4-二甲基吡啶 -3-基) -3，3-二甲基丁酰胺的制 备
Figure imgf000053_0001
Example thirty nine N-(6-(4,5-Dihydrothieno[2,3-c]pyridine-6(7H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Preparation of methylbutyric acid
Figure imgf000053_0001
6-(4，6-二甲基 -5-硝基吡啶 -2-基) -4，5，6，7-四氢噻吩并 [2，3-c]吡啶 （化合物 39A)  6-(4,6-Dimethyl-5-nitropyridin-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (Compound 39A)
本品由 4，5，6，7-四氢噻吩并 [2，3-c]吡啶和 6-氯 -2,4-二甲基 -3-硝基吡啶按照化合物 1B的制 备方法合成， 收率 79%。  This product is synthesized from 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 6-chloro-2,4-dimethyl-3-nitropyridine according to the preparation method of compound 1B. The rate is 79%.
6-(4，5-二氢噻吩并 [2，3-c]吡啶 -6(7H)-基) -2,4-二甲基吡啶 -3-胺 （化合物 39B)  6-(4,5-Dihydrothieno[2,3-c]pyridine-6(7H)-yl)-2,4-dimethylpyridine-3-amine (Compound 39B)
本品由化合物 39A按照化合物 1C的制备方法合成， 收率 98%。  This product was synthesized from Compound 39A according to the preparation method of Compound 1C, yield 98%.
N-(6-(4，5-二氢噻吩并 [2，3-c]吡啶 -6(7H)-基) -2,4-二甲基吡啶 -3-基) -3,3-二甲基丁酰胺（化合 物 39)  N-(6-(4,5-Dihydrothieno[2,3-c]pyridine-6(7H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Methylbutyramide (compound 39)
本品由化合物 39B按照化合物 2的制备方法合成，收率 73%。MS: 358.2 (M+H+). 1H NMR (CDCls, 400 MHz): δ 7.12 (d， J= 5.2 Hz 1H), 6.90 (d, J= 4.8 Hz 1H), 6.61 (brs, 1H), 6.41 (s， 1H)， 4.75 (s, 2H), 3.87 (t, J= 5.6 Hz, 2H), 2.79 (t, J= 5.6 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 2H), 2.16 (s, 3H), 1.12 (s， 9H). This product was synthesized from Compound 39B according to the preparation method of Compound 2, yield 73%. MS: 358.2 (M+H + ). 1H NMR (CDCls, 400 MHz): δ 7.12 (d, J = 5.2 Hz 1H), 6.90 (d, J = 4.8 Hz 1H), 6.61 (brs, 1H), 6.41 (s, 1H), 4.75 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 2H) , 2.16 (s, 3H), 1.12 (s, 9H).
实施例四十  Example forty
N- (4- (6，7-二氢噻吩 [3，4-C]吡啶 -5 (4H) -基） -2，6-二甲基苯基） -3,3-二甲基丁酰胺的制 N-(4-(6,7-Dihydrothiophene[3,4- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide System
Figure imgf000053_0002
Figure imgf000053_0002
4-溴噻吩 -3-甲酸乙酯 （化合物 40A)  Ethyl 4-bromothiophene-3-carboxylate (Compound 40A)
3， 4-二溴噻吩 （2.3 mL， 20.9 mmol) 溶于四氢呋喃 （40 mL) ， 在冰水浴下加入异丙基 氯化镁 （2.0 M的四氢呋喃溶液， 13 mL， 26 mmol) ， 继续搅拌 5小时。 在冷却下加入氯甲 酸乙酯 （2.5 mL， 26 mmol) ， 缓慢升至室温继续搅拌 16小时。 加入 5 mL水再继续搅拌 10 分钟。 真空旋干四氢呋喃， 并用乙酸乙酯 （200 mL)稀释， 再加入 1 N盐酸调节 pH近中性。 分离有机相并用饱和食盐水洗涤， 无水硫酸钠干燥， 过滤旋干， 得化合物 40A的粗产物（3.3 g， 67%收率） 。 3,4-Dibromothiophene (2.3 mL, 20.9 mmol) was dissolved in tetrahydrofuran (40 mL). EtOAc (EtOAc (EtOAc) Ethyl chloroformate (2.5 mL, 26 mmol) was added under cooling and the mixture was slowly warmed to room temperature and then stirred for 16 hr. Add 5 mL of water and continue stirring for 10 minutes. The tetrahydrofuran was spun dry under vacuum and diluted with ethyl acetate (200 mL), and then 1N hydrochloric acid was added to adjust pH to near neutral. The organic phase was separated and washed with brine, dried over anhydrous sodium sulfate
4- (2-乙酰胺基乙烯基） 噻吩 -3-甲酸乙酯 （化合物 40B)  4-(2-acetamidovinyl)thiophene-3-carboxylic acid ethyl ester (Compound 40B)
化合物 40A ( 1.5 g, 6.38 mmol)溶于 N， N-二甲基甲酰胺和三乙胺的混合溶液（V, 4/1， 20 mL) ， 分别加入三 （2-甲基苯基） 膦 （388 mg， 1.28 mmol) ， N-乙烯基乙酰胺 （2.7 g， 31.9 mmol)和醋酸钯（143 mg， 0.638 mmol) ， 在氮气保护下加热至 80 °C反应 12小时。 冷 却至室温， 倒入适量水中， 并用乙酸乙酯 （3x50 mL) 萃取， 合并有机相， 用饱和食盐水洗 涤， 无水硫酸镁干燥， 过滤， 旋干， 柱层析（石油醚： 乙酸乙酯 =3 : 1 )得到化合物 40B ( 1.55 g， 99%收率） 。  Compound 40A (1.5 g, 6.38 mmol) was dissolved in a mixed solution of N,N-dimethylformamide and triethylamine (V, 4/1, 20 mL), respectively, and tris(2-methylphenyl)phosphine was added. (388 mg, 1.28 mmol), N-vinylacetamide (2.7 g, 31.9 mmol) and palladium acetate (143 mg, 0.638 mmol), heated to 80 ° C for 12 hours under nitrogen. The mixture was cooled to room temperature, poured into aq. EtOAc (EtOAc (EtOAc) (EtOAc) =3 : 1 ) Compound 40B (1.55 g, 99% yield) was obtained.
4- (2-乙酰胺基乙基） 噻吩 -3-甲酸乙酯 （化合物 40C)  4-(2-Acetylaminoethyl)thiophene-3-carboxylic acid ethyl ester (Compound 40C)
化合物 40B ( 1.55 g, 6.37 mmol) 溶于甲醇 （20 mL) ， 加入钯碳催化剂 （800 mg) 常压 氢化 12小时。 过滤除去催化剂， 旋干溶液得化合物 40C的粗产物 （1.5 g， 96%收率） 。  Compound 40B (1.55 g, 6.37 mmol) was dissolved in methanol (20 mL). The catalyst was removed by filtration, and the solution was evaporated to dryness mjjjjjjjj
4- (2-胺基乙基） 噻吩 -3-甲酸盐酸盐 （化合物 40D)  4-(2-Aminoethyl)thiophene-3-formate (Compound 40D)
化合物 40C粗品 （lOO mg, 0.41 mmol)加入到 10 mL 2 N盐酸中， 回流 12小时， 真空下 浓縮得化合物 40D， 无需纯化直接投入下一步反应。  The crude compound 40C (100 mg, 0.41 mmol) was added to 10 mL of 2N hydrochloric acid and refluxed for 12 hr and concentrated under vacuo to give compound 40D, which was taken directly to the next reaction without purification.
6,7-二氢噻吩 [3，4-c]吡啶 -4 ( 5H) -酮 （化合物 40E)  6,7-Dihydrothiophene [3,4-c]pyridine -4 ( 5H) -ketone (Compound 40E)
化合物 40D溶于吡啶 （5 mL) ， 加入 N，N-二环己基碳二亚胺 （250 mg， 1.2 mmol) ， 室 温下继续搅拌 12小时。 过滤除去不溶物， 旋干溶剂， 柱层析得化合物 40E ( 60 mg, 两步收 率 93%) 。  Compound 40D was dissolved in pyridine (5 mL), N,N-dicyclohexylcarbodiimide (250 mg, 1.2 mmol) was added and stirring was continued at room temperature for 12 hours. The insoluble material was removed by filtration, and the solvent was evaporated to give a compound 40E (60 mg, yield: 93%).
4，5，6，7-四氢噻吩 [3，4-c]口比啶 （化合物 40F)  4,5,6,7-tetrahydrothiophene [3,4-c]pyridinium (compound 40F)
化合物 40E溶于四氢呋喃 （5 mL) ， 加入硼烷-四氢呋喃络合物（2 mL， 1 M的四氢呋喃 溶液， 2 mmol) ， 加热至回流反应 14小时， 冷却至室温， 再加入 2 mL 1M的氯化氢甲醇溶 液， 加热至回流反应 4小时。 冷却至室温， 将其倒入饱和碳酸氢钠溶液中， 并用二氯甲烷萃 取两次， 合并有机相用水、 饱和食盐水洗涤， 无水硫酸钠干燥， 旋干， 柱层析 （石油醚： 乙 酸乙酯 =1 : 1 ) 得化合物 40F (42 mg, 77%收率） 。  The compound 40E was dissolved in tetrahydrofuran (5 mL), borane-tetrahydrofuran complex (2 mL, 1 M in tetrahydrofuran, 2 mmol) was added and heated to reflux for 14 hours, cooled to room temperature, and then 2 mL of 1 M hydrogen chloride was added. The methanol solution was heated to reflux for 4 hours. The mixture was cooled to room temperature, poured into a saturated aqueous solution of sodium bicarbonate and extracted twice with dichloromethane. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate Ethyl ester = 1 : 1 ) gave compound 40F (42 mg, 77% yield).
N- (4- ( 6,7-二氢噻吩 [3，4-C]吡啶 -5 (4H) -基） -2,6-二甲基苯基） -3,3-二甲基丁酰胺 （化 合物 40) N-(4-(6,7-Dihydrothiophene[3,4- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 40)
本品由化合物 40F和 N- (4-溴 -2， 6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的制 备方法合成， 9%收率。 1H NMR (400 MHz, DMSO) δ: 8.84(s, 1H), 7.20-7.30(m, 2H), 6.38(s, 2H), 4.85-4.93(m, 1H)， 4.34(dd, J = 13.2 Hz, J = 115 Hz, 2H), 2.16(s, 2H), 2.10(s, 6H)， 1.35-1.40(m, 3H), 1.05(s， 9H). This product was synthesized from Compound 40F and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of Compound 5, 9% yield. 1H NMR (400 MHz, DMSO) δ: 8.84 (s, 1H), 7.20-7.30 (m, 2H), 6.38 (s, 2H), 4.85-4.93 (m, 1H), 4.34 (dd, J = 13.2 Hz , J = 115 Hz, 2H), 2.16(s, 2H), 2.10(s, 6H), 1.35-1.40(m, 3H), 1.05(s, 9H).
实施例四 ^一  Embodiment 4 ^1
N-(4-( -二氢噻吩 [2，3-c]吡啶 -6(7H)-基) -2，6-二甲 -3，3-二甲基丁酰胺的制备
Figure imgf000055_0001
Preparation of N-(4-(-dihydrothiophene[2,3-c]pyridine-6(7H)-yl)-2,6-dimethyl-3,3-dimethylbutanamide
Figure imgf000055_0001
3-(2-氨基)噻吩盐酸盐 （化合物 41A)  3-(2-Amino)thiophene hydrochloride (Compound 41A)
将噻吩 -3-基 -乙腈 （2.0 g， 16.2 mmol) 溶于四氢呋喃 （36 mL) 中，慢慢加入硼烷-二甲硫醚 复合物 （3.0 mL， 30.4 mmol)， 反应混合物加热到回流反应 16小时。 恢复室温， 缓慢加入甲醇 淬灭反应。然后再加入饱和的氯化氢 /甲醇溶液 （10 mL)，室温搅拌 20分钟，浓縮得固体初品， 用***（20 mL) 洗涤，过滤得化合物 41A为白色固体 （2.5 g， 收率 94%)。 MS: 128.1 [M+H]+. The thiophen-3-yl-acetonitrile (2.0 g, 16.2 mmol) was dissolved in tetrahydrofuran (36 mL), borane-dimethyl sulfide complex (3.0 mL, 30.4 mmol) was slowly added, and the reaction mixture was heated to reflux. 16 hours. After returning to room temperature, the reaction was quenched by the slow addition of methanol. Then, a saturated hydrogen chloride/methanol solution (10 mL) was added, and the mixture was stirred at room temperature for 20 minutes, and concentrated to give a solid solid, which was washed with diethyl ether (20 mL) to afford Compound 41A as a white solid (2.5 g, yield 94%) . MS: 128.1 [M+H] + .
3-(2-甲酰胺基乙基)噻吩盐酸盐 （化合物 41B)  3-(2-carboxamidoethyl)thiophene hydrochloride (Compound 41B)
将化合物 41A(1.3 g，7.7 mmol) 溶于甲酸乙酯 （25 mL) 中，反应混合物加热到回流反应 3 小时。 浓縮， 残渣用二氯甲烷和水溶解， 分液， 有机相依次用 2 N 稀盐酸 （l x 40 mL) 和饱 和食盐水 （l x 40 mL) 洗涤， 无水硫酸钠干燥， 过滤， 浓縮得化合物 41B粗品 （0.98 g， 收率 82%), 不纯化直接投入下一步反应。 MS: 156.1 [M+H]+. Compound 41A (1.3 g, 7.7 mmol) was dissolved in ethyl acetate (25 mL). Concentrate, the residue is dissolved in dichloromethane and water, and the organic phase is washed with 2 N diluted hydrochloric acid (1×40 mL) and brine (1×40 mL), dried over anhydrous sodium sulfate The crude compound 41B (0.98 g, yield 82%) was taken directly to the next reaction without purification. MS: 156.1 [M+H] + .
3，4-二氢噻吩并 [2，3-c]吡啶 （化合物 41C)  3,4-dihydrothieno[2,3-c]pyridine (Compound 41C)
将化合物 41B (0.98 g， 6.3 mmol) 溶于乙腈 (15 mL) 中， 加入三氯氧磷 (1.0 mL, 11.0 mmol), 然后室温反应 4小时。 反应混合物浓縮， 残渣用水溶解， 水相用***洗涤， 然后用 浓氨水调节至碱性。水相用二氯甲烷萃取 （3 x 30 mL)， 合并有机相， 饱和食盐水 （l x 40 mL) 洗涤， 无水硫酸钠干燥， 过滤， 浓縮得化合物 41C (0.68 g， 收率 78%)。 MS: 138.1 [M+H]+. Compound 41B (0.98 g, 6.3 mmol) was dissolved in EtOAc (15 mL). The reaction mixture was concentrated, the residue was dissolved in water, and the aqueous phase was washed with diethyl ether. The aqueous phase was extracted with methylene chloride (3×30 mL). EtOAcjjjjjjjjjj . MS: 138.1 [M+H] + .
4，5，6，7-四氢噻吩并 [2，3-c]吡啶 （化合物 41D)  4,5,6,7-tetrahydrothieno[2,3-c]pyridine (Compound 41D)
将化合物 41C (0.68 g， 5.0 mmol) 溶于甲醇 (15 mL) 中， 加入硼氢化钠 (0.32 g, 8.4 mmol), 然后室温反应 2小时。 缓慢加入水淬灭反应， 浓縮， 残渣用水溶解， 水相用乙酸乙 酯萃取 （3 x 30 mL)， 合并有机相， 饱和食盐水 （l x 40 mL) 洗涤， 无水硫酸钠干燥， 过滤， 浓縮得化合物 41D (0.68 g， 收率 98%)。 MS: 140.1 [M+H]+. Compound 41C (0.68 g, 5.0 mmol) was dissolved in methanol (15 mL), sodium borohydride (0.32 g, 8.4 mmol). The reaction mixture was quenched with EtOAc (3 mL, EtOAc). Concentration gave compound 41D (0.68 g, yield 98%). MS: 140.1 [M+H] + .
N-(4-(4，5-二氢噻吩 [2，3-c]吡啶 -6(7H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 41 ) 本品由化合物 41D和 N- (4-溴代 -2， 6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5 的制备方法合成， 收率 70% o MS: 357.3 [M+H]+. 1H NMR (CDC13， 400 MHz): δ 7.13 (d，J= 5.2 Hz 1H)， 6.80 (d, J= 5.2 Hz 1H), 6.69 (s, 2H), 6.53 (brs, 1H), 4.41 (s, 2H), 3.56 (t, J= 5.6 Hz, 2H), 2.81 (t，J= 5.6 Hz, 2H), 2.26 (s， 2H), 2.20 (s， 6H)， 1.14 (s， 9H). MS: 357.2 (M+H+). 实施例四十二 N-(4-(4,5-Dihydrothiophene[2,3-c]pyridine-6(7H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 41) This product was synthesized from Compound 41D and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of Compound 5, yield 70% o MS: 357.3 [M+H] + . 1H NMR (CDC1 3 , 400 MHz): δ 7.13 (d, J = 5.2 Hz 1H), 6.80 (d, J = 5.2 Hz 1H), 6.69 (s, 2H) , 6.53 (brs, 1H), 4.41 (s, 2H), 3.56 (t, J = 5.6 Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H), 2.26 (s, 2H), 2.20 (s, 6H), 1.14 (s, 9H). MS: 357.2 (M+H + ). Example forty two
N-(4-(6，7-二氢噻吩 [3， 2-c]吡啶 -5 ( 4H) -基) )-2， 6-二甲基苯基） -3， 3-二甲基丁酰胺（化 合物 42 ) 的制备
Figure imgf000056_0001
N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl))-2,6-dimethylphenyl)-3,3-dimethylbutyl Preparation of amide (compound 42)
Figure imgf000056_0001
本品由 4，5，6，7-四氢噻吩[3，2-0 |吡啶和 ( 4善 2， 6-二甲基苯基) -3， 3-二甲基丁酰胺 按照化合物 5的制备方法合成， 16% 收率。 MS: 357.2 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.15 (d, J = 5.2 Hz, 1H), 6.85 ( d， J = 5.2 Hz, 1H) ， 6.74 ( s, 2H) ， 6.55 (s, 1H), 4.30 (s, 2H), 3.59-3.62 (t, Ji = 6 Hz, J2= 5.6 Hz, 1H), 3.00 (brs, 2H), 2.30 (s, 2H), 2.24 (s, 6H)， 1.17 (s, 9H). 实施例四十三 This product consists of 4,5,6,7-tetrahydrothiophene [3,2-0 |pyridine and (4 good 2,6-dimethylphenyl)-3,3-dimethylbutanamide according to compound 5 Preparation method synthesis, 16% yield. MS: 357.2 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.15 (d, J = 5.2 Hz, 1H), 6.85 ( d, J = 5.2 Hz, 1H) , 6.74 ( s, 2H ), 6.55 (s, 1H), 4.30 (s, 2H), 3.59-3.62 (t, Ji = 6 Hz, J 2 = 5.6 Hz, 1H), 3.00 (brs, 2H), 2.30 (s, 2H), 2.24 (s, 6H), 1.17 (s, 9H). Example forty-three
N-(4-(6，7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)-基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺的制 备
Figure imgf000056_0002
N-(4-(6,7-Dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3- Preparation of dimethylbutyramide
Figure imgf000056_0002
叔丁基 6，7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)-羧酸酯 （化合物 43A)  tert-Butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Compound 43A)
将 (E)-叔丁基 3 二甲氨基)甲叉基 )-4-哌啶酮 -1-羧酸酯 (3 g， 1 1.8 1^^1)溶于甲醇(50 11^) 中， 缓慢加入水合肼 (0.3 mL， 1.25 eq)。 反应混合物被加热到回流反应 1小时后， 冷却至室温， 浓縮， 残渣用乙酸乙酯溶解， 水洗， 食盐水洗， 无水硫酸钠干燥， 过滤， 旋干得到化合物 43A 为白色固体 （2.30 g， 88%)。  (E)-tert-Butyl 3 dimethylamino)methylidene)-4-piperidone-1-carboxylate (3 g, 1 1.8 1^^1) was dissolved in methanol (50 11^), Hydrazine hydrate (0.3 mL, 1.25 eq) was added slowly. The reaction mixture was heated to reflux for 1 hr, then cooled to EtOAc EtOAc (EtOAc m. 88%).
4，5，6，7-四氢 -1H-卩比唑并 [4，3-c]卩比啶 （化合物 43B )  4,5,6,7-tetrahydro-1H-indolezolo[4,3-c]indolepyridinium (Compound 43B)
将化合物 43A (0.44 g， 2 mmol)溶于二氯甲烷 (10 mL)中， 加入三氟乙酸 (1 mL)。 室温反应 3小时后， 浓縮， 得到化合物 43B为白色固体 C0.7 g， 100%)。  Compound 43A (0.44 g, 2 mmol) was dissolved in dichloromethane (10 mL). After reacting for 3 hours at room temperature, it was concentrated to give Compound 43B as a white solid.
N-(4-(6，7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺（化合 物 43 )  N-(4-(6,7-Dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3- Dimethylbutyramide (compound 43)
本品由化合物 43B和 N- ( 4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的 制备方法合成， 20%收率。 MS: 341.5 [M+H]+. 1H NMR (400 MHz, CD3OD) δ: 7.42 (s, 1H), 6.97 (s， 2H), 4.23 (s， 2H), 3.58 (t， J= 5.6 Hz, 2H), 2.82 (t， J= 5.6 Hz, 2H), 2.28 (s， 2H), 2.18 (s， 6H)， 1.12 (s, 9H). This product was synthesized from Compound 43B and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of Compound 5, 20% yield. MS: 341.5 [M+H] + . 1H NMR (400 MHz, CD 3 OD) δ: 7.42 (s, 1H), 6.97 (s, 2H), 4.23 (s, 2H), 3.58 (t, J = 5.6 Hz, 2H), 2.82 (t, J= 5.6 Hz, 2H), 2.28 (s, 2H), 2.18 (s, 6H), 1.12 (s, 9H).
实施例四十四 N-(2，6-二甲基 -4-(l-甲基 -6,7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)-基)苯基) -3,3-二甲基丁酰 胺的制备
Figure imgf000057_0001
Embodiment 44 N-(2,6-Dimethyl-4-(l-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)phenyl) Preparation of -3,3-dimethylbutanamide
Figure imgf000057_0001
1-甲基 -6,7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)- 叔丁基羧酸酯 （化合物 44A)  1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-tert-butylcarboxylate (Compound 44A)
向溶有 6，7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)- 叔丁基羧酸酯 （550 mg， 2.5 mmol)的四氢 呋喃 （20 mL)溶液中依次缓慢加入氢化钠 (150 mg， 1.5 eq)和碘甲烷 (150 /L， 1.2 eq)。 室温搅拌 To a solution of 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-tert-butylcarboxylate (550 mg, 2.5 mmol) in tetrahydrofuran (20 mL) Sodium hydride (150 mg, 1.5 eq) and methyl iodide (150 / L, 1.2 eq) were added slowly. Stirring at room temperature
3小时， 加水淬灭反应， 乙酸乙酯萃取， 有机相用饱和食盐水洗涤后用无水硫酸钠干燥。 过 滤， 滤液浓縮得甲基化异构体化合物 44A和化合物 45A的混合物 (500 mg)。 粗产物直接用于 下一步反应。 After 3 hours, the reaction was quenched with EtOAc (EtOAc)EtOAc. After filtration, the filtrate was concentrated to give a mixture of methylated isomer compound 44A and compound 45A (500 mg). The crude product was used directly in the next reaction.
1-甲基 -6,7-二氢 -1H-吡唑并 [4，3-c]吡啶 （化合物 44B)  1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine (Compound 44B)
将所得化合物 44A和化合物 45A的混合物 （0.50 g)溶于 5 mL三氟乙酸中， 室温搅拌 3 小时。 反应结束后， 直接减压蒸干溶剂得黄色固体， 即化合物 44B和化合物 45B的三氟乙酸 盐的混合物 (0.93 g， 100%)。 粗产物直接用于下一步反应。  A mixture of the obtained compound 44A and compound 45A (0.50 g) was dissolved in 5 ml of trifluoroacetic acid, and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals The crude product was used directly in the next reaction.
N-(2，6-二甲基 -4-(1-甲基 -6,7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)-基)苯基) -3,3-二甲基丁酰 胺 （化合物 44)  N-(2,6-Dimethyl-4-(1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)phenyl) -3,3-dimethylbutyramide (Compound 44)
本品由化合物 44B和化合物 45B的三氟乙酸盐的混合物和 N- (4-溴代 -2， 6-二甲基苯基） -3, 3-二甲基丁酰胺按照化合物 5的制备方法合成，收率 40%。 MS: 355.5 [M+H]+.1H NMR (400 MHz, CDCls) δ: 7.67 (s, 1H), 7.39 (s, 1H), 6.94 (s, 1H), 4.32 (s, 2H), 3.79 (s, 3H), 3.68 (t, J= 5.6 Hz, 2H), 3.28 (t，J= 5.6 Hz, 2H), 2.29 (s， 2H), 2.16 (s， 6H)， 1.09 (s， 9H). NOESY(H→H): CH， δΗ = 7.67 (CH2, δΗ= 4.32); CHX 2, δΗ= 6.94 (CH2, δΗ= 4.32, CH2， δΗ= 3.67); CH3, δΗ= 3.79 (CH2， δΗ = 2.94); CH2, δΗ= 2.94 (CH3, δΗ= 3.79, CH2， δΗ= 3.67). This product is prepared from a mixture of compound 44B and compound 45B trifluoroacetate and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to compound 5. Method synthesis, yield 40%. MS: 355.5 [M + H] + .1H NMR (400 MHz, CDCls) δ: 7.67 (s, 1H), 7.39 (s, 1H), 6.94 (s, 1H), 4.32 (s, 2H), 3.79 ( s, 3H), 3.68 (t, J = 5.6 Hz, 2H), 3.28 (t, J = 5.6 Hz, 2H), 2.29 (s, 2H), 2.16 (s, 6H), 1.09 (s, 9H). NOESY(H→H): CH, δ Η = 7.67 (CH 2 , δ Η = 4.32); CHX 2, δ Η = 6.94 (CH 2 , δ Η = 4.32, CH 2 , δ Η = 3.67); CH 3 , δ Η = 3.79 (CH 2 , δ Η = 2.94); CH 2 , δ Η = 2.94 (CH 3 , δ Η = 3.79, CH 2 , δ Η = 3.67).
Figure imgf000057_0002
Figure imgf000057_0002
实施例四十五  Example forty five
Ν-(2，6-二甲基 -4-(2-甲基 -6,7-二氢 -2Η-吡唑并 [4，3-c]吡啶 -5(4Η)-基)苯基) -3,3-二甲基丁酰 胺的制备
Figure imgf000058_0001
Ν-(2,6-Dimethyl-4-(2-methyl-6,7-dihydro-2Η-pyrazolo[4,3-c]pyridine-5(4Η)-yl)phenyl) Preparation of -3,3-dimethylbutanamide
Figure imgf000058_0001
2-甲基 -6，7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)- 叔丁基羧酸酯 （化合物 45A)  2-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-tert-butylcarboxylate (Compound 45A)
本品由 6，7-二氢 -1H-吡唑并 [4，3-c]吡啶 -5(4H)- 叔丁基羧酸酯按照化合物 44A的制备方法 合成， 得到化合物 44A和化合物 45A的混合物。  This product is synthesized from 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-tert-butylcarboxylate according to the preparation method of compound 44A to obtain compound 44A and compound 45A. mixture.
2-甲基 -6,7-二氢 -1H-吡唑并 [4，3-c]吡啶 （化合物 45B)  2-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine (Compound 45B)
本品由化合物 44A和化合物 45A的混合物按照化合物 44B的制备方法合成，得到化合物 44B和化合物 45B的混合物。  This product is synthesized from a mixture of the compound 44A and the compound 45A according to the preparation method of the compound 44B to give a mixture of the compound 44B and the compound 45B.
N-(2，6-二甲基 -4-(2-甲基 -6,7-二氢 -2H-吡唑并 [4，3-c]吡啶 -5(4H)-基)苯基) -3,3-二甲基丁酰 胺 （化合物 45 )  N-(2,6-Dimethyl-4-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-yl)phenyl) -3,3-dimethylbutyramide (compound 45)
本品由化合物 44B和化合物 45B的三氟乙酸盐的混合物和 N- (4-溴代 -2， 6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的制备方法合成，收率 10%。 MS: 355.5 [M+H]+.1H NMR (400 MHz, CDCls) δ: 7.82 (s, 1H), 7.29 (s, 1H), 7.05 (s, 1H), 4.41 (s, 2H), 3.90 (s, 3H), 3.65 (t, J= 5.6 Hz, 2H), 3.04 (t, J= 5.6 Hz, 2H), 2.30 (s， 2H), 2.17 (s， 6H)， 1.10 (s, 9H). This product is prepared from a mixture of compound 44B and compound 45B trifluoroacetate and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to compound 5. Method synthesis, yield 10%. MS: 355.5 [M + H] + .1H NMR (400 MHz, CDCls) δ: 7.82 (s, 1H), 7.29 (s, 1H), 7.05 (s, 1H), 4.41 (s, 2H), 3.90 ( s, 3H), 3.65 (t, J = 5.6 Hz, 2H), 3.04 (t, J = 5.6 Hz, 2H), 2.30 (s, 2H), 2.17 (s, 6H), 1.10 (s, 9H).
实施例四十六  Example forty six
N-(2, 6-二甲基 -4- (1-甲基 -6， 7-二氢 -1H-吡咯 [3， 2-c]吡啶 -5(4H)-基)苯基) -3， 3-二甲基 丁酰胺
Figure imgf000058_0002
N-(2,6-Dimethyl-4-(1-methyl-6,7-dihydro-1H-pyrrole[3,2-c]pyridine-5(4H)-yl)phenyl)-3 , 3-dimethylbutanamide
Figure imgf000058_0002
(E)-l-甲基 -2-(2-硝基乙烯基) -1H-吡咯 （化合物 46A)  (E)-l-methyl-2-(2-nitrovinyl)-1H-pyrrole (Compound 46A)
在圆底烧瓶中加入 1-甲基 -1H-吡咯 -2-甲醛 C4 g， 50 mmol), 硝基甲烷 （；75 mL)， 醋酸铵 (3.85 g, 50 mmol 回流 4小时， TLC 检测反应结束， 减压蒸出溶剂。加入 lOOmL乙酸乙酯， 水洗 (50mL)，饱和氯化钠洗 (50mL)，有机层用无水硫酸钠干燥，减压蒸出溶剂得到化合物 46A (6.5 g 85%收率）。  In a round bottom flask, 1-methyl-1H-pyrrole-2-carbaldehyde C4 g, 50 mmol), nitromethane (75 mL), ammonium acetate (3.85 g, 50 mmol reflux for 4 hours, TLC detection The solvent was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Rate).
2-(1-甲基 -1H-吡咯 -2-基)乙胺 （化合物 46B)  2-(1-methyl-1H-pyrrol-2-yl)ethylamine (Compound 46B)
本品由化合物 46A按照化合物 5G的制备方法合成， 81.9%收率。 MS: 166  This product was synthesized from Compound 46A according to the preparation method of Compound 5G, yield 81.9%. MS: 166
[M+42(CH3CN)]+. [M+42(CH 3 CN)] + .
N-(2-(l-甲基 -1H-吡咯 -2-基)乙基)甲酰胺 （化合物 46C) 本品由化合物 46B和甲酸乙酯按照化合物 41B的制备方法合成， 33.8% 收率。 MS: 153 [M+H]+. N-(2-(l-methyl-1H-pyrrol-2-yl)ethyl)carboxamide (Compound 46C) This product was synthesized from the compound 46B and ethyl formate according to the preparation method of the compound 41B, with a yield of 33.8%. MS: 153 [M+H]+.
1-甲基 -6， 7-二氢 -1H-吡咯 [3， 2-c]吡啶 （化合物 46D)  1-methyl-6,7-dihydro-1H-pyrrole [3,2-c]pyridine (Compound 46D)
本品由化合物 46C按照化合物 41C的制备方法合成， 22.6%收率。 MS: 135 [M+H]+. 1-甲基 -4， 5， 6， 7-四氢 -1H-吡咯 [3， 2-c] 吡啶 (化合物 46E) This product was synthesized from Compound 46C according to the method for the preparation of Compound 41C, 22.6% yield. MS: 135 [M+H] + . 1-Methyl-4,5,6,7-tetrahydro-1H-pyrrole[3,2-c]pyridine (Compound 46E)
本品由化合物 46D按照化合物 41D的制备方法合成， 49%收率。 MS: 137 [M+H]+. This product was synthesized from Compound 46D according to the preparation method of Compound 41D, 49% yield. MS: 137 [M+H] + .
N-(2, 6-二甲基 -4- (1-甲基 -6， 7-二氢 -1H-吡咯 [3， 2-c]吡啶 -5(4H)-基)苯基) -3， 3-二甲基 丁酰胺 （化合物 46)  N-(2,6-Dimethyl-4-(1-methyl-6,7-dihydro-1H-pyrrole[3,2-c]pyridine-5(4H)-yl)phenyl)-3 , 3-dimethylbutyramide (Compound 46)
本品由化合物 46E和 N-(4-溴 -2,6-二甲基苯) -3,3-二甲基丁酰胺按照化合物 5的制备方法 合成， 45%收率。 MS: 354[M+H]+. 1HNMR (d6-OMSO 400ΜΗζ)δ: 9.14 (9.14， brs 1Η)， 7.12(d,lH: J=3.2), 6.68(d， 1H， J=2), 5.88 (d， 2H， J=2.4), 4.34 (s, 2H), 3.76 (s, 2H), 3.50 (s, 3H), 2.87 (s, 2H): 2.21 (s, 2H), 2.15 (s, 6H)， 1.06 (s, 9H). This product was synthesized from compound 46E and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 5, 45% yield. MS: 354 [M+H] + . 1HNMR (d6-OMSO 400 ΜΗζ) δ: 9.14 (9.14, brs 1 Η), 7.12 (d, lH : J=3.2), 6.68 (d, 1H, J=2), 5.88 (d, 2H, J=2.4), 4.34 (s, 2H), 3.76 (s, 2H), 3.50 (s, 3H), 2.87 (s, 2H) : 2.21 (s, 2H), 2.15 (s, 6H) ), 1.06 (s, 9H).
实施例四十七  Example forty seven
N- (4- (2，3-二氢 -1H-吡咯 [2，3-b]吡啶小基） -2，6-二甲基苯基） -3，3-二甲基丁酰胺 （化合 物 47) 的制备
Figure imgf000059_0001
N-(4-(2,3-dihydro-1H-pyrrole[2,3-b]pyridine small)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (compound Preparation of 47)
Figure imgf000059_0001
本品由二氢 -7-氮杂吲哚和 N-(4-溴 -2， 6-二甲基苯) -3， 3-二甲基丁酰胺按照化合物 5的制备 方法合成， 30%收率。 1HNMR (CDC13, 400 MHz): δ 7.98-8.02 (m， 1H), 7.49 (s, 2H),7.31-7.32 (m， 1H), 6.64 (brs, 1H), 6.59-6.60 (m， 1H), 4.03 (t，_/ = 8.5 ,2H), 3.14 (t = 8,5 ,2H), 2.62 (s， 6H)， 1.15 (s， 9H).MS: 338 (M+H+). This product is synthesized from dihydro-7-azaindole and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 5, 30% rate. 1HNMR (CDC1 3 , 400 MHz): δ 7.98-8.02 (m, 1H), 7.49 (s, 2H), 7.31-7.32 (m, 1H), 6.64 (brs, 1H), 6.59-6.60 (m, 1H) , 4.03 (t, _/ = 8.5, 2H), 3.14 (t = 8,5,2H), 2.62 (s, 6H), 1.15 (s, 9H).MS: 338 (M+H + ).
实施例四十八  Example forty eight
N-(2，6-二甲基 -4-(3- (三氟甲基) -5,6-二氢 -[1，2，4]*** [4，3-a]吡嗪 -7(8H)-基)苯基) -3,3-二甲 基丁酰胺 （化合物
Figure imgf000059_0002
N-(2,6-Dimethyl-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7 (8H)-yl)phenyl)-3,3-dimethylbutanamide (compound)
Figure imgf000059_0002
本品由 3- (三氟甲基) -5，6，7，8-四氢 -[1，2，4]*** [4，3-a]吡嗪的盐酸盐和 N- (4-溴代 -2,6-二甲 基苯基） -3， 3-二甲基丁酰胺按照化合物 5的制备方法合成， 6.1%收率。 MS 410.2 (M+H+). 1H NMR (400 MHz，CDCl3) δ: 6.71 (s，， 2H), 6.68(s， 1H), 4.59 (s， 2H), 4.26 (m， 2H), 3.71 (m， 2H), 2.30 (s， 2H), 2.25 (s， 6H)， 1.17 (s, 9H). This product consists of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride and N- (4 -Bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide was synthesized according to the preparation method of compound 5, 6.1% yield. MS 410.2 (M+H + ). 1H NMR (400 MHz, CDCl 3 ) δ: 6.71 (s,, 2H), 6.68 (s, 1H), 4.59 (s, 2H), 4.26 (m, 2H), 3.71 (m, 2H), 2.30 (s, 2H), 2.25 (s, 6H), 1.17 (s, 9H).
实施例四十九  Example forty-nine
N-(4-(5，6-二氢 -[1，2，4]***并 [4，3-a] 吡嗪 -7(8H)-基) -2,6-二甲基 )-3，3-二甲基丁酰胺的制备
Figure imgf000060_0001
N-(4-(5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-2,6-dimethyl)- Preparation of 3,3-dimethylbutanamide
Figure imgf000060_0001
2-氯 -3-肼基吡嗪 （化合物 49A)  2-Chloro-3-mercaptopyrazine (Compound 49A)
水合肼 （20 mL，43.6 mmol) 慢慢滴加到 2,3-二氯吡嗪 （3.2 g， 21.8 mmol) 的乙醇 （600 mL) 溶液中， 升温至回流反应 1.5 小时， 减压旋干， 固体加到水中， 过滤， 固体在乙醇中重 结晶两次得到黄色固体（2.68 g， 产率 85%)。  Hydrazine hydrate (20 mL, 43.6 mmol) was slowly added dropwise to a solution of 2,3-dichloropyrazine (3.2 g, 21.8 mmol) in ethanol (600 mL), warmed to reflux for 1.5 h, and dried under reduced pressure. The solid was added to water, filtered, and then crystallised from EtOAc (EtOAc)
8-氯***并 [4，3-a]吡嗪 （化合物 49B)  8-Chlorotriazolo[4,3-a]pyrazine (Compound 49B)
化合物 49A加入到原甲酸三甲酯中， 升温至回流反应 10 小时， 冷却至室温， 过滤， 得 到化合物 49B固体 C2 g， 收率 70%)。  Compound 49A was added to trimethyl orthoformate, and the mixture was warmed to reflux for 10 hours, cooled to room temperature, and filtered to give compound 49B solid C2 g (yield 70%).
5，6，7，8-四氢 -[1，2，4]***并 [4，3-a]吡嗪 （化合物 49C)  5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (Compound 49C)
化合物 49B (2.0 g， 13.0 mmol)， 二氧化铂 (1 g) 及钯碳 (0.4 g) 加入到甲醇 (100 mL) 中， 在 50 psi条件下氢化 14个小时， 过滤， 有机溶剂减压旋干， 得到化合物 49C为棕色固体产 物 （1.4 g， 收率 88%)。  Compound 49B (2.0 g, 13.0 mmol), platinum dioxide (1 g) and palladium on carbon (0.4 g) were added to methanol (100 mL), hydrogenated at 50 psi for 14 hours, filtered, and the organic solvent was evaporated. Drying gave Compound 49C as a brown solid (1.4 g, yield 88%).
N-(4-(5，6-二氢 -[1，2，4]***并 [4，3-a] 吡嗪 -7(8H)-基) -2,6-二甲基 )-3，3-二甲基丁酰胺 （化合 物 49)  N-(4-(5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-2,6-dimethyl)- 3,3-dimethylbutyramide (compound 49)
本品由化合物 49C和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的 制备方法合成，收率 17%。 MS: 342 (M+H+). 1HNMR (DMSO, 400 MHz): δ 8.95 (s, 1H), 8.87 (s， 1H), 6.81 (s, 2H), 4.60 (s, 2H), 4.21 (t, J= 5.6 Hz, 2H), 3.72 (t, J = 4.2 Hz, 2H), 2.17 (s, 2H), 2.10 (s， 6H)， 1.05 (s， 8H). This product was synthesized from compound 49C and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 5, yield 17%. MS: 342 (M+H + ). 1H NMR (DMSO, 400 MHz): δ 8.95 (s, 1H), 8.87 (s, 1H), 6.81 (s, 2H), 4.60 (s, 2H), 4.21 (t , J = 5.6 Hz, 2H), 3.72 (t, J = 4.2 Hz, 2H), 2.17 (s, 2H), 2.10 (s, 6H), 1.05 (s, 8H).
实施例五十  Example fifty
N-(4-(3，4-二氢吡咯并 [l，2-a] 吡嗪 -2(1H)-基) -2，6-二甲基 )-3，3-二甲基丁酰胺的制备
Figure imgf000060_0002
N-(4-(3,4-dihydropyrrolo[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethyl)-3,3-dimethylbutanamide Preparation
Figure imgf000060_0002
( 1H-吡咯 -1- 基） 乙胺 （化合物 50A) 1H-吡咯 （2.09 mL， 30 mmol),氢氧化钠 （6.0 g， 150 mmol)及 TBAS (四丁基硫酸氢铵， 0.51 g， 1.5 mmol)加入到乙腈 （30 mL) 中， 室温搅拌 30 分钟， 加入 2-氯乙胺盐酸盐 （4.18 g， 36 mmol), 升温至回流反应 24 小时， 加入水 （lOO mL), 乙酸乙酯萃取 C100 mLx3)， 无水硫酸 钠干燥， 减压旋干， 二氯甲浣 /甲醇纯化得到化合物 50A (2.66 g，收率 81%)。 (1H-pyrrol-1-yl)ethylamine (Compound 50A) 1H-pyrrole (2.09 mL, 30 mmol), sodium hydroxide (6.0 g, 150 mmol) and TBAS (tetrabutylammonium hydrogen sulfate, 0.51 g, 1.5 mmol) were added to acetonitrile (30 mL) and stirred at room temperature for 30 min. Add 2-chloroethylamine hydrochloride (4.18 g, 36 mmol), warm to reflux for 24 hours, add water (100 mL), extract ethyl acetate (100 mL×3), dry over anhydrous sodium sulfate Purification of methylene chloride/methanol afforded compound 50A (2.66 g, yield 81%).
1,2,3,4 - 四氢吡咯并 [l，2-a]吡嗪 （化合物 50B)  1,2,3,4 -tetrahydropyrrolo[l,2-a]pyrazine (Compound 50B)
化合物 50A (2.1 g， 19.1 mmol) 及 37% 的甲醛溶液 (0.53 mL, 19.1 mmol) 加入到乙醇 (30 ml) 中，滴加三氟乙酸（1.2 ml),升温至 50 °C反应 15 分钟，冷却到 25 °C在反应 4小时， 减压旋干， 二氯甲浣 /甲醇纯化得到化合物 50B (932 mg， 收率 40%)。  Compound 50A (2.1 g, 19.1 mmol) and 37% formaldehyde solution (0.53 mL, 19.1 mmol) were added to ethanol (30 ml), trifluoroacetic acid (1.2 ml) was added dropwise, and the mixture was warmed to 50 ° C for 15 minutes. The mixture was cooled to 25 ° C for 4 hours, dried under reduced pressure, and purified with methylene chloride/methanol to afford compound 50B (932 mg, yield 40%).
N-(4-(3，4-二氢吡咯并 [l，2-a] 吡嗪 -2(1H)-基) -2,6-二甲基 )-3，3-二甲基丁酰胺 （化合物 50) 本品由化合物 50B和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的 制备方法合成，收率 34%。 MS: 338 (M-H+). 1HNMR (CDC13, 400 MHz): δ 6.70 (s, 2H), 6.59-6.91 (m， 1H)， 6.54 (s， 1H), 6.17-9.19 (m， 1H), 5.94-5.96 (m， 1H), 4.39 (s， 2H), 3.62 (t， J= 4.2 Hz, 2H), 3.62 (t, J= 4.2 Hz, 2H), 2.28 (s， 2H), 2.20 (s， 6H)， 1.14 (s， 9H). N-(4-(3,4-dihydropyrrolo[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethyl)-3,3-dimethylbutanamide (Compound 50) This product was synthesized from Compound 50B and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of Compound 5, yield 34% . MS: 338 (M-H+). 1HNMR (CDC1 3 , 400 MHz): δ 6.70 (s, 2H), 6.59-6.91 (m, 1H), 6.54 (s, 1H), 6.17-9.19 (m, 1H) , 5.94-5.96 (m, 1H), 4.39 (s, 2H), 3.62 (t, J = 4.2 Hz, 2H), 3.62 (t, J = 4.2 Hz, 2H), 2.28 (s, 2H), 2.20 ( s, 6H), 1.14 (s, 9H).
实施例五 ^一  Embodiment 5 ^1
N-(2，6-二甲基 -4-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基异吲哚 -2(3H)-基)苯基) -3，3-二甲基丁酰胺 的盐酸盐的制备
Figure imgf000061_0001
N-(2,6-Dimethyl-4-(3a,4,7,7a-tetrahydro-1Η-4,7-vinylisoindole-2(3H)-yl)phenyl)-3, Preparation of 3-dimethylbutyramide hydrochloride
Figure imgf000061_0001
3a，4，7，7a-四氢 -1Η-4，7-乙烯基异吲哚 -1，3 (2H) -二酮 （化合物 51A)  3a,4,7,7a-tetrahydro-1Η-4,7-vinylisoindole-1,3(2H)-dione (Compound 51A)
8g (99.9mmol， leq) 环己二烯溶于 20ml苯中在 5 °C条件下加入 9.7g (99.9mmol， leq) 马来酰亚胺的苯（100ml)溶液中。 反应边搅拌边缓慢升温至回流， 回流 3小时。 降温至 0°C， 沉淀过滤， 真空旋干溶剂， 得到化合物 51A。  8 g (99.9 mmol, leq) of cyclohexadiene was dissolved in 20 ml of benzene and added to a solution of 9.7 g (99.9 mmol, leq) of maleimide in benzene (100 ml) at 5 °C. The reaction was slowly heated to reflux while stirring, and refluxed for 3 hours. The temperature was lowered to 0 ° C, the precipitate was filtered, and the solvent was evaporated in vacuo to give Compound 51A.
2，3，3a，4，7，7a-六氢 -1Η-4，7-乙烯基异吲哚 （化合物 51B)  2,3,3a,4,7,7a-hexahydro-1Η-4,7-vinylisoindole (Compound 51B)
本品由化合物 51A按照化合物 5G的制备方法合成， 收率 91%。  This product was synthesized from Compound 51A according to the preparation method of Compound 5G, yield 91%.
N-(2，6-二甲基 -4-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基异吲哚 -2(3H)-基)苯基) -3,3-二甲基丁酰胺 盐酸盐 （化合物 51 )  N-(2,6-Dimethyl-4-(3a,4,7,7a-tetrahydro-1Η-4,7-vinylisoindole-2(3H)-yl)phenyl)-3, 3-dimethylbutyramide hydrochloride (Compound 51)
本品由化合物 51B和 N- (4-溴代 -2， 6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 7 的制备方法合成， 收率 30% 1H NMR (400 MHz, CDC13) δ: 6.98 (s, 1H)， 6.47 (s, 1H)， 6.26 (s， 2H), 6.15 (t， J = 3.2 Hz, 2H), 3.49 (t， J = 3.2 Hz, 2H), 2.80 (dd， J! = 8.8 Hz, J2 = 4.8 Hz, 2H), 2.62 (m， 2H), 2.25 (s, 2H), 2.17 (s, 3H), 1.52 (m， 2H), 1.24-1.29 (m， 2H), 1.13 (s, 9H). MS: 404.0 [M+H]+. This product is synthesized from compound 51B and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 7, yield 30% 1H NMR (400 MHz, CDC1 3 ) δ: 6.98 (s, 1H), 6.47 (s, 1H), 6.26 (s, 2H), 6.15 (t, J = 3.2 Hz, 2H), 3.49 (t, J = 3.2 Hz, 2H ), 2.80 (dd, J! = 8.8 Hz, J 2 = 4.8 Hz, 2H), 2.62 (m, 2H), 2.25 (s, 2H), 2.17 (s, 3H), 1.52 (m, 2H), 1.24-1.29 (m, 2H), 1.13 (s, 9H). MS: 404.0 [M+H ] + .
实施例五十二  Example fifty-two
N-(4- (六氢 -1Η-4，7-乙烯基异吲哚 -2(3H)-基) -2，6-二甲基 )-3，3-二甲基丁酰胺的盐酸盐（化合 物 52) 的制备
Figure imgf000062_0001
Hydrochloric acid of N-(4-(hexahydro-1Η-4,7-vinylisoindole-2(3H)-yl)-2,6-dimethyl)-3,3-dimethylbutanamide Preparation of salt (compound 52)
Figure imgf000062_0001
本品由 N-(2，6-二甲基 -4-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基异吲哚 -2(3H)-基)苯基) -3,3-二甲基 丁酰胺按照化合物 29B的制备方法合成， 之后用盐酸***溶液处理得其盐酸盐的白色固体， 收率 87 NMR (400 MHz, CDC13) δ: Ί .21 (s, 1Η), 7.05 (s, 1H), 3.80 (t， J= 10.4 Hz, 2H), 3.28 (t，J= 9.2 Hz, 2H), 2.63 (m， 2H), 2.25 (s, 2H), 2.17 (s, 3H), 1.49-1.72 (m， 10H), 1.13 (s, 9H). MS: 406.0 [M+H]+. This product consists of N-(2,6-dimethyl-4-(3a,4,7,7a-tetrahydro-1Η-4,7-vinylisoindole-2(3H)-yl)phenyl) -3,3-Dimethylbutanamide was synthesized according to the preparation method of Compound 29B, and then was treated with diethyl ether hydrochloride to give a white solid of the hydrochloride salt, yield NMR (400 MHz, CDC1 3 ) δ: Ί .21 ( s, 1Η), 7.05 (s, 1H), 3.80 (t, J= 10.4 Hz, 2H), 3.28 (t, J= 9.2 Hz, 2H), 2.63 (m, 2H), 2.25 (s, 2H), 2.17 (s, 3H), 1.49-1.72 (m, 10H), 1.13 (s, 9H). MS: 406.0 [M+H] + .
实施例五十三  Example fifty three
N-(4，6-二甲基 -2-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基)嘧啶 -5-基) -3，3-二甲 基叔丁
Figure imgf000062_0002
N-(4,6-Dimethyl-2-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindol-2(3H)-yl)pyrimidine-5- -3,3-dimethyl tert-butyl
Figure imgf000062_0002
2-(4，6-二甲基 -5-硝基嘧啶 -2-基) -2，3，3a，4，7，7a-六氢 -1Η-4，7-乙烯基异吲哚 （化合物 53A) 6-氯 -2,4-二甲基 -3-硝基嘧啶 （282 mg， 1.5 mmol), 2，3，3a，4，7，7a-六氢 -1Η-4，7-乙烯基异吲哚 (225 mg, 1.5 mmol) 及碳酸钾 （414 mg， 3.0 mmol) 溶于 5 mL DMF中， 100°C搅拌 16 h。 反应完毕后加入 50 mL水， 乙酸乙酯萃取， 干燥浓縮后， 粗品使用石油醚 /乙酸乙酯 =10: 1纯 化得到化合物 53A为白色固体 （400 mg， 89%收率） 。  2-(4,6-Dimethyl-5-nitropyrimidin-2-yl)-2,3,3a,4,7,7a-hexahydro-1Η-4,7-vinylisoindole (compound 53A) 6-Chloro-2,4-dimethyl-3-nitropyrimidine (282 mg, 1.5 mmol), 2,3,3a,4,7,7a-hexahydro-1Η-4,7-vinyl Isoindole (225 mg, 1.5 mmol) and potassium carbonate (414 mg, 3.0 mmol) were dissolved in 5 mL of DMF and stirred at 100 ° C for 16 h. After completion of the reaction, 50 mL of water was added, and ethyl acetate was evaporated. EtOAcjjjjjjj
4，6-二甲基 -2-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基)嘧啶 -5-胺（化合物 53B) 化合物 53A (400 mg, 1.3 mmol) 与氯化铵 （209 mg， 3.9 mmol)和锌粉 （255 mg， 3.9 mmol)溶于 50 mL甲醇及 I mL水中， 70 °C反应 1小时， 反应完成后， 过滤除去固体， 滤液 经减压蒸干后， 得到化合物 53B粗品， 直接用于下一步反应 （567mg， 100%收率） 。  4,6-Dimethyl-2-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindole-2(3H)-yl)pyrimidine-5-amine (compound) 53B) Compound 53A (400 mg, 1.3 mmol) was dissolved in 50 mL of methanol and 1 mL of water with ammonium chloride (209 mg, 3.9 mmol) and zinc powder (255 mg, 3.9 mmol) for 1 hour at 70 °C. After completion, the solid was removed by filtration, and the filtrate was evaporated to dryness, mjjjjjj
N-(4，6-二甲基 -2-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基)嘧啶 -5-基) -3,3-二甲 基叔丁酰胺盐酸盐 （化合物 53 )  N-(4,6-Dimethyl-2-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindol-2(3H)-yl)pyrimidine-5- -3,3-dimethyl-tert-butylamide hydrochloride (compound 53)
本品由化合物 53B和 3，3-二甲基丁酰氯按照化合物 1的制备方法合成， 26%收率。 MS: 369 This product was synthesized from Compound 53B and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 1, with a yield of 26%. MS: 369
[M+l]+. 1H NMR (400 MHz, DMSO- 6) δ: 9.43 (brs, 1H), 7.42 (t, J= 3.6 Hz, 2H), 3.74 (m， 2H), 3.25 (d, J= 14.0 Hz, 2H), 2.65(s,4H),2.26 (s， 6H)， 2.23 (s， 2H), 1.51 (d, J= 7.2 Hz, 2H), 1.18 (m,2H),1.04 (s， 9H). [M+l] + . 1H NMR (400 MHz, DMSO-6) δ: 9.43 (brs, 1H), 7.42 (t, J = 3.6 Hz, 2H), 3.74 (m, 2H), 3.25 (d, J = 14.0 Hz, 2H), 2.65 (s, 4H), 2.26 (s, 6H), 2.23 (s, 2H), 1.51 (d, J = 7.2 Hz, 2H), 1.18 (m, 2H) ), 1.04 (s, 9H).
实施例五十四  Embodiment fifty four
N-(2- (六氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基) -4，6-二甲基嘧啶 -5-基) -3，3-二甲基丁酰胺 盐酸盐 （化合物 54)
Figure imgf000063_0001
N-(2-(hexahydro-1Η-4,7-vinyltetrahydroisoindole-2(3H)-yl)-4,6-dimethylpyrimidin-5-yl)-3,3-di Methylbutyramide hydrochloride (Compound 54)
Figure imgf000063_0001
本品由 N-(4，6-二甲基 -2-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基)嘧啶 -3- 基) -3,3-二甲基丁酰胺按照化合物 40C的制备方法合成， 70% 收率。 MS: 371 [M+l]+. 1H NMR (400 MHz, DMSO- 6) δ: 9.46 (s, 1H), 3.71 (m， 4H)， 2.29 (s, 6H)， 2.23 (s, 2H), 1.53 (m， 8H)， 1.26 (m，4H)，1.05 (s， 9H). This product consists of N-(4,6-dimethyl-2-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindol-2(3H)-yl)pyrimidine -3-yl)-3,3-dimethylbutanamide was synthesized according to the preparation method of compound 40C, 70% yield. MS: 371 [M+l] + . 1H NMR (400 MHz, DMSO-6) δ: 9.46 (s, 1H), 3.71 (m, 4H), 2.29 (s, 6H), 2.23 (s, 2H), 1.53 (m, 8H), 1.26 (m, 4H), 1.05 (s, 9H).
实施例五十五  Example fifty five
N-(2，4-二甲基 -6-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-yl)吡啶 -3-yl)-3，3-二甲 基丁酰 的制备
Figure imgf000063_0002
N-(2,4-Dimethyl-6-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindol-2(3H)-yl)pyridine-3- Preparation of yl)-3,3-dimethylbutyryl
Figure imgf000063_0002
2，3，3a，4，7，7a-六氢 -1Η-4，7-乙烯基异吲哚 （化合物 55A)  2,3,3a,4,7,7a-hexahydro-1Η-4,7-vinylisoindole (Compound 55A)
本品由 3a，4，7，7a-四氢 -1Η-4，7-乙烯基异吲哚 -1，3(2H)-二酮按照化合物 5G的制备方法合 成， 收率 91%。  This product is synthesized from 3a, 4,7,7a-tetrahydro-1Η-4,7-vinylisoindole-1,3(2H)-dione according to the preparation method of compound 5G, yield 91%.
2-(4，6-二甲级 -5-硝基吡啶 -2-基) -2，3，3a，4，7，7a-六氢 -1Η-4，7-乙烯基异吲哚 （化合物 55B) 本品由 6-氯 -2,4-二甲基 -3-硝基吡啶和化合物 55A按照化合物 53A的制备方法合成， 85% 收率。  2-(4,6-Dimethyl-5-nitropyridin-2-yl)-2,3,3a,4,7,7a-hexahydro-1Η-4,7-vinylisoindole (compound) 55B) This product was synthesized from 6-chloro-2,4-dimethyl-3-nitropyridine and compound 55A according to the preparation method of compound 53A, 85% yield.
2，4-二甲基 -6-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基) B比啶 -3-胺（化合物 55C) 化合物 55B、 氯化铵和锌粉按照化合物 53B的制备方法合成， 得到化合物 55C粗品， 直 接用于下一步反应， 100%收率。  2,4-Dimethyl-6-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindole-2(3H)-yl) B-pyridin-3-amine (Compound 55C) Compound 55B, ammonium chloride and zinc powder were synthesized according to the method for the preparation of compound 53B to give crude compound 55C, which was directly used for the next reaction, 100% yield.
N-(2，4-二甲基 -6-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基) B比啶 -3-基) -3,3-二甲 基丁酰胺盐酸盐 （化合物 55 )  N-(2,4-Dimethyl-6-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindol-2(3H)-yl) B-pyridine- 3-yl)-3,3-dimethylbutyramide hydrochloride (Compound 55)
本品由化合物 55C和 3，3-二甲基丁酰氯按照化合物 1的制备方法合成， 30% 收率。 MS: 368 [M+l]+. 1H NMR (400 MHz, DMSO- 6) δ: 12.30 (s, 1H), 9.59 (s, 1H), 6.81 (s, 1H), 6.25 (t， J = 8.0 Hz, 2H), 3.74-3.78 (m， 2H), 3.29 (d， J= 13.2 Hz, 2H), 2.72 (d, J= 3.6 Hz, 2H), 2.65(s,2H), 2.39 (s， 3H), 2.26 (s， 2H), 2.21 (s， 3H), 1.53 (d, J= 7.6 Hz, 2H), 1.19-1.24 (m,2H), 1.04 (s， 9H). 实施例五十六 This product was synthesized from Compound 55C and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 1, 30% yield. MS: 368 [M+l] + . 1H NMR (400 MHz, DMSO-6) δ: 12.30 (s, 1H), 9.59 (s, 1H), 6.81 (s, 1H), 6.25 (t, J = 8.0 Hz, 2H), 3.74-3.78 (m, 2H), 3.29 (d, J= 13.2 Hz, 2H), 2.72 (d, J= 3.6 Hz, 2H), 2.65(s,2H), 2.39 (s , 3H), 2.26 (s, 2H), 2.21 (s, 3H), 1.53 (d, J = 7.6 Hz, 2H), 1.19-1.24 (m, 2H), 1.04 (s, 9H). six
N-(6- (六氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3H)-基) -2，4-二甲基吡啶 -3-基) -3，3-二甲基丁酰胺 盐酸盐 （化合物 56) 的制备
Figure imgf000064_0001
N-(6-(hexahydro-1Η-4,7-vinyltetrahydroisoindol-2(3H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Preparation of methylbutyramide hydrochloride (Compound 56)
Figure imgf000064_0001
本品由 Ν-(2，4-二甲基 -6-(3a，4，7，7a-四氢 -1Η-4，7-乙烯基四氢异吲哚 -2(3Η)-基) Β比啶 -3- 基) -3,3-二甲基丁酰胺按照化合物 40C的制备方法合成， 54% 收率。 MS: 370 [M+l]+. 1H NMR (400 MHz, DMSO- 6) δ: 12.51 (s， 1H), 9.64 (s， 1H), 6.95 (s， 1H), 3.73 (s， 2H), 2.58 (s， 2H): 2.44 (s, 3H), 2.26 (s, 2H), 2.24 (s, 3H), 1.57 (s, 8H)， 1.24-1.40 (m,4H), 1.07 (s, 9H). This product consists of Ν-(2,4-dimethyl-6-(3a,4,7,7a-tetrahydro-1Η-4,7-vinyltetrahydroisoindole-2(3Η)-yl) Β The pyridin-3-yl)-3,3-dimethylbutanamide was synthesized according to the method for the preparation of compound 40C in 54% yield. MS: 370 [M+l] + . 1H NMR (400 MHz, DMSO-6) δ: 12.51 (s, 1H), 9.64 (s, 1H), 6.95 (s, 1H), 3.73 (s, 2H), 2.58 (s, 2H) : 2.44 (s, 3H), 2.26 (s, 2H), 2.24 (s, 3H), 1.57 (s, 8H), 1.24-1.40 (m, 4H), 1.07 (s, 9H) .
实施例五十七  Example fifty seven
N-(4- 3-氮杂 -二环 [3.1.0]戊烷) -2，6-二甲基苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000064_0002
Preparation of N-(4- 3-aza-bicyclo[3.1.0]pentane)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000064_0002
3-氮杂 -二环 [3.1.0]戊烷 -2,4-二酮 （化合物 57A)  3-Aza-bicyclo [3.1.0]pentane -2,4-dione (Compound 57A)
3-氧杂 -二环 [3.1.0]戊烷 -2,4-二酮 （2 g， 17.86 mmol) 与尿素 （1.07 g， 17.86 mmol) 溶于 50 mL甲苯， 混合物在封管中加入至 150°C搅拌 4 h， 120°C搅拌 8 h。 反应完成后， 旋干溶剂， 所得化合物 57A为白色固体 （0.7 g， 35%收率） 。  3-oxa-bicyclo[3.1.0]pentane-2,4-dione (2 g, 17.86 mmol) and urea (1.07 g, 17.86 mmol) dissolved in 50 mL of toluene. Stir at 150 ° C for 4 h and at 120 ° C for 8 h. After completion of the reaction, the solvent was evaporated to dryness, m.
3-氮杂 -二环 [3.1.0]戊烷盐酸盐 （化合物 57B)  3-Aza-bicyclo[3.1.0]pentane hydrochloride (Compound 57B)
本品由化合物 57A按照化合物 5G的制备方法合成， 该产物使用***盐酸溶液酸化得化 合物 57B粗品， 该产物直接用于下一步反应中。  This product was synthesized from Compound 57A according to the preparation of Compound 5G. The product was acidified using diethyl ether aqueous hydrochloric acid to give crude compound 57B, which was used directly in the next reaction.
N- (4- (3-氮杂 -二环 [3丄 0]戊烷） -2,6-二甲基苯基） -3,3-二甲基丁酰胺 （化合物 57) 本品由化合物 57B和 N- (4-溴代 -2,6-二甲基苯基） -3,3-二甲基丁酰胺按照化合物 5的制 备方法合成， 67%收率。 MS: 301.3 [M+H]+. 1H NMR (400 MHz, DMSO- 6) δ: 8.82 (s, 1H)， 6.24 (s， 2H), 3.45 (d, J= 9.2 Hz, 2H), 3.20 (d, J= 8.8 Hz, 2H), 2.15 (s， 2H), 2.14 (s， 6H)， 1.66 (t，J= 3.6 Hz, 2H), 1.05 (s， 9H)， 0.68-0.69 (m， 1H), 0.23-0.24 (m， 1H). N-(4-(3-Aza-bicyclo[3丄0]pentane)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 57) This product consists of a compound 57B and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide were synthesized according to the method for the preparation of compound 5, yield 67%. MS: 301.3 [M+H] + . 1H NMR (400 MHz, DMSO-6) δ: 8.82 (s, 1H), 6.24 (s, 2H), 3.45 (d, J = 9.2 Hz, 2H), 3.20 ( d, J = 8.8 Hz, 2H), 2.15 (s, 2H), 2.14 (s, 6H), 1.66 (t, J = 3.6 Hz, 2H), 1.05 (s, 9H), 0.68-0.69 (m, 1H) ), 0.23-0.24 (m, 1H).
实施例五十八  Example fifty eight
N-(4- (十氢喹啉) -3-基) -2， 6-二甲苯基 -3， 3-二甲基丁酰胺盐酸盐的制备
Figure imgf000065_0001
Preparation of N-(4-(decahydroquinolin-3-yl)-2,6-dimethylphenyl-3,3-dimethylbutanamide hydrochloride
Figure imgf000065_0001
N- (2， 6-二甲基 -4- (3-喹啉基） 苯基） -3， 3-二甲基丁酰胺 （化合物 58A)  N-(2,6-Dimethyl-4-(3-quinolinyl)phenyl)-3,3-dimethylbutanamide (Compound 58A)
本品由 3-喹啉硼酸和 N- (4-溴 -2， 6-二甲苯基） -3， 3-二甲基丁酰胺按照化合物 19A的 制备方法合成， 48%收率。 MS: 347.2 (M+H+). This product is synthesized from 3-quinoline boronic acid and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 19A, 48% yield. MS: 347.2 (M+H + ).
N- (4- (十氢喹啉） -3-基） -2， 6-二甲苯基 -3， 3-二甲基丁酰胺盐酸盐 （化合物 58) 本品由化合物 58A按照化合物 15的制备方法， 70°C过夜反应， 4%收率。 MS: 357.3 (M+H+).N-(4-(decahydroquinolin-3-yl)-2,6-dimethylphenyl-3,3-dimethylbutanamide hydrochloride (Compound 58) This product is compound 58A according to compound 15 Preparation method, 70 ° C overnight reaction, 4% yield. MS: 357.3 (M+H + ).
1H NMR (400 MHz, CD3OD) δ: 7.09 (s， 2H), 3.57-3.59 (m， 1H)， 2.92-3.20 (m， 4H)， 2.36 (s， 2H),1H NMR (400 MHz, CD 3 OD) δ: 7.09 (s, 2H), 3.57-3.59 (m, 1H), 2.92-3.20 (m, 4H), 2.36 (s, 2H),
2.28 (s， 6H)， 1.15-2.24 (m， 10H), 1.16 (s, 9H). 2.28 (s, 6H), 1.15-2.24 (m, 10H), 1.16 (s, 9H).
实施例五十九  Example fifty-nine
( S) -N- (4-六氢 -1H-吡啶 [l，2-a]吡嗪 -2 (6H) -基） -2，6-二甲基苯基） -3，3-二甲基丁酰胺 的制备
Figure imgf000065_0002
(S)-N-(4-Hexahydro-1H-pyridine [l,2-a]pyrazine-2(6H)-yl)-2,6-dimethylphenyl)-3,3-dimethyl Preparation of butylbutyramide
Figure imgf000065_0002
( S) -叔丁基 2- ( (2-甲氧基 -2-氧乙基） 氨基甲酰基） 哌啶 -1-羧酸盐 （化合物 59A) 在反应瓶中加入 N-Boc-L-哌啶 -2-羧酸 （5.3 g， 23 mmol)， 甘氨酸甲酯盐酸盐（2.92 g， 23 mmol) ， i-乙基- (J-二甲基氨基丙基） 碳二亚胺盐酸盐 （ 5.34 g， 27.9 mmol) 和 1-羟基苯并 ***（3.77 g， 27.9 mmol)的二氯甲烷 （lOO mL)溶液中， 搅拌下加入三乙胺 （6.5 mL， 46.6 mmol) ， 该反应液在室温下搅拌过夜。 反应完毕后， 减压蒸馏掉大部分溶剂， 向该残留物中 加入水（lOO mL)， 乙酸乙酯萃取（200 mL)分液， 有机相分别用 5%的柠檬酸（4 x 60 mL)， 10%的碳酸钾 （2 x l00 mL) ， 饱和的食盐水， 无水硫酸钠干燥， 旋干后得到无色结晶状化合 物 59A粗品， 直接用于下一步反应。  (S)-tert-Butyl 2-((2-methoxy-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (Compound 59A) Add N-Boc-L- to the reaction flask Piperidine-2-carboxylic acid (5.3 g, 23 mmol), glycine methyl ester hydrochloride (2.92 g, 23 mmol), i-ethyl-(J-dimethylaminopropyl) carbodiimide hydrochloride To a solution of the salt (5.34 g, 27.9 mmol) and 1-hydroxybenzotriazole (3.77 g, 27.9 mmol) in dichloromethane (100 mL), triethylamine (6.5 mL, 46.6 mmol) The solution was stirred at room temperature overnight. After the reaction was completed, most of the solvent was distilled off under reduced pressure. Water (100 mL) was added to the residue, and ethyl acetate (200 mL) was partitioned. The organic phase was separated from 5% citric acid (4 x 60 mL) , 10% potassium carbonate (2 x l00 mL), saturated brine, dried over anhydrous sodium sulfate, and dried to give the crude product of product 59A as colorless crystals.
( S) -甲基 2- (哌啶 -2-酰胺基） 乙酸盐 （化合物 59B)  (S)-Methyl 2-(piperidin-2-amido)acetate (Compound 59B)
将化合物 59A粗品和盐酸的***溶液 （7M， 50 mL) 在室温下搅拌三个小时。 反应完毕 后， 旋干得到化合物 59B粗产品， 未经纯化直接用于下一步反应。  The crude compound 59A and a solution of hydrochloric acid in diethyl ether (7M, 50 mL) were stirred at room temperature for three hours. After completion of the reaction, the crude product of Compound 59B was obtained by spin-drying, and was used for the next reaction without purification.
( S) -六氢 -1H-吡啶 [l，2-a]吡嗪 -1，4 (6H) -二酮 （化合物 59C)  (S)-Hexahydro-1H-pyridine [l,2-a]pyrazine-1,4 (6H)-dione (Compound 59C)
将化合物 59B粗品加入到有无水甲醇 （lOO mL) 的圆底烧瓶中， 搅拌下加入三乙胺 （10 mL, 72 mmol) ， 反应液回流过夜。 反应结束后， 旋干溶剂， 粗产品用异丙醇重结晶， 得到 化合物 59C为白色的针状结晶 （1.0 g， 三步收率 29%) 。 ( S) -八氢 -IH-吡啶 [l，2-a]吡嗪 （化合物 59D) The crude compound 59B was added to a round-bottomed flask with anhydrous methanol (100 mL), triethylamine (10 mL, After completion of the reaction, the solvent was evaporated to dryness, and the crude product was crystallised from isopropyl alcohol to afford white crystals (yield: (S)-octahydro-IH-pyridine [l,2-a]pyrazine (Compound 59D)
本品由化合物 59C按照化合物 5G的制备方法合成， 52%收率。  This product was synthesized from Compound 59C according to the preparation method of Compound 5G, 52% yield.
( S) -N- (4-六氢 -1H-吡啶 [l，2-a]吡嗪 -2 (6H) -基） -2,6-二甲基苯基） -3,3-二甲基丁酰胺 (化合物 59)  (S)-N-(4-Hexahydro-1H-pyridine [l,2-a]pyrazine-2(6H)-yl)-2,6-dimethylphenyl)-3,3-dimethyl Butylamide (Compound 59)
本品由化合物 59D和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的 制备方法合成， 30% 收率。 MS: 358 (M+H+) .1H NMR (400 MHz, DMSO) δ: 10.89 (s, IH), 8.98 (s， lH) , 6.72(s, 2H), 3.80-3.77 (m， 2H), 3.76-3.07 (m， 7H)， 2.51 (s, 2H), 2.50 (s, 6H)， 2.10-1.48 (m， 6H)， 1.05 (s， 9H).  This product was synthesized from Compound 59D and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation of Compound 5 in 30% yield. MS: 358 (M+H+) .1H NMR (400 MHz, DMSO) δ: 10.89 (s, IH), 8.98 (s, lH), 6.72 (s, 2H), 3.80-3.77 (m, 2H), 3.76 -3.07 (m, 7H), 2.51 (s, 2H), 2.50 (s, 6H), 2.10-1.48 (m, 6H), 1.05 (s, 9H).
实施例六十  Embodiment 60
( S) -N- (4- (六氢吡咯 [l，2-a]吡嗪 -2 ( IH) -基） -2，6-二甲基苯基） -3，3-二甲基丁酰胺 的制
Figure imgf000066_0001
(S)-N-(4-(hexahydropyrrole[l,2-a]pyrazine-2(IH)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide system
Figure imgf000066_0001
( S) 叔丁基 2- ( (甲氧基 -2-氧乙基） 酰基甲胺） 吡咯烷 -1-羧酸盐 （化合物 60Α) 本品由 Boc-L-脯氨酸和甘氨酸甲酯盐酸盐按照化合物 59A的制备方法合成，得粗品直接 投下步反应。  (S) tert-Butyl 2-((methoxy-2-oxoethyl) acylmethylamine)pyrrolidine-1-carboxylate (Compound 60Α) This product consists of Boc-L-proline and glycine methyl ester The hydrochloride salt was synthesized according to the preparation method of Compound 59A, and the crude product was directly subjected to a step reaction.
( S) -甲基 2- (吡咯烷 -2-酰胺基） 乙酸盐 （化合物 60B)  (S)-Methyl 2-(pyrrolidin-2-amido)acetate (Compound 60B)
本品由化合物 60A按照化合物 59B的制备方法合成， 得粗品直接投下步反应。  This product is synthesized from the compound 60A according to the preparation method of the compound 59B, and the crude product is directly subjected to a step reaction.
( S) -六氢吡咯 [l，2-a]吡嗪 -1,4-二酮 （化合物 60C)  (S)-hexahydropyrrole [l,2-a]pyrazine-1,4-dione (Compound 60C)
本品由化合物 60B粗品按照化合物 59C的制备方法合成， 三步收率 28%。  This product was synthesized from the crude compound 60B according to the preparation method of compound 59C. The yield in three steps was 28%.
( S) -八氢吡咯 [l，2-a]吡嗪 （化合物 60D)  (S)-octahydropyrrole [l,2-a]pyrazine (Compound 60D)
本品由化合物 60C按照化合物 5G的制备方法合成， 52%收率。  This product was synthesized from Compound 60C according to the preparation method of Compound 5G, yield 52%.
( S) -N- (4- (六氢吡咯 [l，2-a]吡嗪 -2 ( 1H) -基） -2,6-二甲基苯基） -3,3-二甲基丁酰胺 (化合物 60)  (S)-N-(4-(hexahydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide (compound 60)
本品由化合物 60D和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5的 制备方法合成， 30% 收率。 MS: 344 (M+H+). 1H NMR (400 MHz, DMSO) δ: 11.45-11.53 (m, IH), 8.99 (s，lH) ， 6.74 (s， IH) ， 6.69 (s， 1H)， 4.05〜3.01 (m， 9H)， 2.52 (s， 2H)， 2.51 (s， 6H)， 2.50〜1.73 (m， 3H), 1.05 (s， 9H). This product was synthesized from Compound 60D and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of Compound 5 in 30% yield. MS: 344 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 11.45-11.53 (m, IH), 8.99 (s,lH), 6.74 (s, IH), 6.69 (s, 1H), 4.05~3.01 (m, 9H), 2.52 (s, 2H), 2.51 (s, 6H), 2.50~1.73 (m, 3H), 1.05 (s, 9H).
实施例六 ^一 ( S) -N- (6- (六氢吡咯 [l，2-a]吡嗪 -2 ( IH) -基) -2，4-二甲基吡啶 -3-基) -3， 3-二甲基丁 酰胺的制备
Figure imgf000067_0001
Embodiment 6^ (S)-N-(6-(hexahydropyrrole[l,2-a]pyrazine-2(IH)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Preparation of methylbutyric acid
Figure imgf000067_0001
( S) -2- (4,6-二甲基 -5-硝基吡啶 -2-基） 八氢吡咯 [l，2-a]吡嗪 （化合物 61A)  (S)-2-(4,6-Dimethyl-5-nitropyridin-2-yl)octahydropyrrole [l,2-a]pyrazine (Compound 61A)
本品由 （S) -八氢吡咯 [l，2-a]吡嗪和 2-氯 -4， 6-二甲基 -5-硝基吡啶按照化合物 2A的制备 方法合成， 46% 收率。  This product was synthesized from (S)-octahydropyrrole [l,2-a]pyrazine and 2-chloro-4,6-dimethyl-5-nitropyridine according to the preparation method of Compound 2A, 46% yield.
( S) -6-六氢吡咯 [l，2-a]吡嗪 -2 ( 1H) -基） -2,4-二甲基吡啶 -3-胺 （化合物 61B) 本品由化合物 61A按照化合物 1C的制备方法合成， 粗品直接投下步反应。  (S)-6-hexahydropyrrole [l,2-a]pyrazine-2(1H)-yl)-2,4-dimethylpyridin-3-amine (Compound 61B) This product is compounded from compound 61A The preparation method of 1C is synthesized, and the crude product is directly subjected to a step reaction.
( S) -N- (6- (六氢吡咯 [l，2-a]吡嗪 -2 ( 1H) -基) -2,4-二甲基吡啶 -3-基) -3， 3-二甲基丁 酰胺 （化合物 61 )  (S)-N-(6-(hexahydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-di Methylbutyramide (compound 61)
本品由化合物 61B和 3，3-二甲基丁酰氯按照化合物 2的制备方法合成， 两步收率 70%。 MS: 345.3 (M+H+). 1H NMR (400 MHz, DMSO) δ: 12.01-11.81 (m， IH), 9.7 (s， IH), 7.16 (s， IH) 5.20〜2.97(m， 9H)， 2.49 (d, J= 16 Ηζ,ΙΗ), 2.23 (s， 5H)， 2.15〜1.70 (m， 4H)， 1.05 (s， 9H). This product is synthesized from compound 61B and 3,3-dimethylbutyryl chloride according to the preparation method of compound 2, and the yield in two steps is 70%. MS: 345.3 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 12.01-11.81 (m, IH), 9.7 (s, IH), 7.16 (s, IH) 5.20~2.97 (m, 9H) , 2.49 (d, J= 16 Ηζ, ΙΗ), 2.23 (s, 5H), 2.15~1.70 (m, 4H), 1.05 (s, 9H).
实施例六十二  Embodiment sixty two
( S) -N- (6- (六氢 -IH-吡啶并 [l，2-a]吡嗪 -2 (6H) -基） -2，4-二甲基吡啶 -3-基） -3,3-二 甲基丁酰胺的制备
Figure imgf000067_0002
(S)-N-(6-(hexahydro-IH-pyrido[l,2-a]pyrazine-2(6H)-yl)-2,4-dimethylpyridin-3-yl)-3 , 3-dimethylbutyramide preparation
Figure imgf000067_0002
( S) -2- (4,6-二甲基 -5-硝基吡啶 -2-基） 八氢 -1H-吡啶并 [l，2-a]吡嗪 （化合物 62 A ) 本品由 （S) -八氢 -1H-吡啶并 [l，2-a]吡嗪和 2-氯 -4， 6-二甲基 -5-硝基吡啶按照化合物 2A 的制备方法合成， 47%收率。  (S)-2-(4,6-Dimethyl-5-nitropyridin-2-yl) octahydro-1H-pyrido[l,2-a]pyrazine (Compound 62 A) S) - octahydro-1H-pyrido[l,2-a]pyrazine and 2-chloro-4,6-dimethyl-5-nitropyridine were synthesized according to the procedure for the preparation of compound 2A, 47% yield.
( S) -6- (六氢 -1H-吡啶 [l，2-a]吡嗪 -2 (6H) -基） -2,4-二甲基吡啶 -3-胺 （化合物 62B) 本品由化合物 62A按照化合物 1C的制备方法合成， 粗品直接投下步反应。  (S)-6-(hexahydro-1H-pyridine [l,2-a]pyrazine-2(6H)-yl)-2,4-dimethylpyridin-3-amine (Compound 62B) Compound 62A was synthesized according to the preparation method of Compound 1C, and the crude product was directly subjected to a step reaction.
( S) -N- (6- (六氢 -1H-吡啶并 [l，2-a]吡嗪 -2 (6H) -基） -2,4-二甲基吡啶 -3-基） -3,3-二 甲基丁酰胺 （化合物 62)  (S)-N-(6-(hexahydro-1H-pyrido[l,2-a]pyrazine-2(6H)-yl)-2,4-dimethylpyridin-3-yl)-3 ,3-dimethylbutyramide (compound 62)
本品由化合物 62B和 3，3-二甲基丁酰氯按照化合物 2的制备方法合成， 两步收率 70%。 MS: 359.3 (M+H+). 1H NMR (400 MHz, DMSO) δ: 11.2 (s, IH), 9.46 (s, IH), 7.06 (s, IH), 4.46 (d: j = 12.8 Hz, IH), 3.50-2.93 (m， 7H), 2.51 (s， 3H), 2.08 (s， 2H), 1.91〜1.23 (m， 6H)， 1.05(s, 9H). 实施例六十三 This product is synthesized from compound 62B and 3,3-dimethylbutyryl chloride according to the preparation method of compound 2, and the yield in two steps is 70%. MS: 359.3 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 11.2 (s, IH), 9.46 (s, IH), 7.06 (s, IH), 4.46 (d : j = 12.8 Hz, IH), 3.50-2.93 (m, 7H), 2.51 (s, 3H), 2.08 (s, 2H), 1.91~1.23 (m, 6H), 1.05(s, 9H). Example sixty three
N- (2， 6-二甲 -4- (吡啶 -2-基） 苯） -3， 3-二甲基丁酰胺盐酸盐 （化合物 63 ) 的制备
Figure imgf000068_0001
Preparation of N-(2,6-dimethyl-4-(pyridin-2-yl)benzene)-3,3-dimethylbutyramide hydrochloride (Compound 63)
Figure imgf000068_0001
本品由 2-溴吡啶和 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 -2-基) 苯基） -3， 3-二甲基丁酰胺按照化合物 20D的制备方法合成， 产品用盐酸***酸化得盐酸盐， 58%收率。 MS: 297.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.43 (brs, 1H), 8.80 (m， 1H)， 8.36 (m， 1H), 8.26 (m， 1H), 7.83 (s， 2H), 7.76 (m， 1H), 2.27 (s， 8H)， 1.08 (s， 9H). This product consists of 2-bromopyridine and N-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl)-3,3-dimethylbutanamide was synthesized according to the procedure for the preparation of compound 20D. The product was acidified with diethyl ether. MS: 297.2 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.43 (brs, 1H), 8.80 (m, 1H), 8.36 (m, 1H), 8.26 (m, 1H), 7.83 (s, 2H), 7.76 (m, 1H), 2.27 (s, 8H), 1.08 (s, 9H).
实施例六十四  Embodiment sixty four
N- (4， 3-氰基 -2-基） -2， 6-二甲基苯） -3， 3-二甲基丁酰胺盐酸盐的制备
Figure imgf000068_0002
Preparation of N-(4,3-cyano-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000068_0002
N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧硼 -2-基） 苯） 3， 3—二甲基丁酰 胺 （化合物 64A)  N-(2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)benzene) 3,3-dimethylene Amide (Compound 64A)
N- (4-溴 -2， 6-二甲基苯） -3， 3-二甲基丁酰胺（2 g， 7 mmol) ， 双 (频哪醇合)二硼 （2 g， 8 mmol) ， 醋酸钾 （2.1 g， 21 mmol) 和 Pd (dppf)2Cl2 ( [1，1， -双 (二苯基膦) 二茂铁]二氯 化钯， 0.3 g， 0.42 mmol)溶于 35 ml的 1， 4-二氧六烷中， 氮气抽换三次， 80°C搅拌 2小时。 过滤有机层，旋干滤液。粗品使用石油醚 /乙酸乙酯 =5:1纯化得到化合物 64A (2 g， 83%收率）。 N-(4-Bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (2 g, 7 mmol), bis(pinacol) diboron (2 g, 8 mmol) , potassium acetate (2.1 g, 21 mmol) and Pd (dppf) 2 Cl 2 ([1,1,-bis(diphenylphosphino)ferrocene]palladium dichloride, 0.3 g, 0.42 mmol) dissolved in 35 In ml of 1,4-dioxane, the nitrogen was exchanged three times and stirred at 80 ° C for 2 hours. The organic layer was filtered and the filtrate was dried. The crude product was purified using petroleum ether / ethyl acetate = 5:1 to afford compound 64A (2 g, 83% yield).
N-(4， 3-氰基 -2-基) -2， 6-二甲基苯) -3， 3-二甲基丁酰胺盐酸盐 （化合物 64)  N-(4,3-Cyano-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide hydrochloride (Compound 64)
本品由 3-氯哌嗪 -2氰基和化合物 64A按照化合物 20D的制备方法合成，产品用盐酸*** 酸化得盐酸盐， 32%收率。 MS: 323.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.39 (s, 1Η)， 9.03 (s， 1Η), 8.88 (s， 1H), 7.66 (s， 1H), 2.28 (m， 8H)， 1.09 (s， 9H).  This product was synthesized from 3-chloropiperazine-2 cyano and compound 64A according to the procedure for the preparation of compound 20D. The product was acidified with diethyl ether. MS: 323.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.39 (s, 1 Η), 9.03 (s, 1 Η), 8.88 (s, 1H), 7.66 (s, 1H), 2.28 (m, 8H), 1.09 (s, 9H).
实施例六十五  Example sixty five
N- (4- (3, 5-二甲基异恶唑 -4-基） -2， 6-二甲基苯） -3， 3-二甲基丁酰胺盐酸盐 （化合 物 65 ) 的制备
Figure imgf000068_0003
本品由 4-溴 -3,5-二甲基异恶唑和 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧 杂硼烷 -2-基） 苯基） -3， 3-二甲基叔丁酰胺按照化合物 20D的制备方法合成， 产品用盐酸乙 醚酸化得盐酸盐， 80%收率。 MS: 315.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.20 (s, 1Η)， 7.08 (s， 2Η), 2.40 (s， 3H), 2.24 (s， 2H), 2.22 (s， 3H), 2.19 (S， 6H)， 1.07 (s， 9H). Preparation of N-(4-(3,5-dimethylisoxazol-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide hydrochloride (Compound 65)
Figure imgf000068_0003
This product consists of 4-bromo-3,5-dimethylisoxazole and N-(2,6-dimethyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2- Dioxaborolan-2-yl)phenyl)-3,3-dimethyl-tert-butanamide was synthesized according to the procedure for the preparation of compound 20D. The product was acidified with diethyl ether. MS: 315.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.20 (s, 1 Η), 7.08 (s, 2 Η), 2.40 (s, 3H), 2.24 (s, 2H), 2.22 (s, 3H), 2.19 (S, 6H), 1.07 (s, 9H).
实施例六十六  Embodiment sixty six
N- (2， 6-二甲基 -4- ( 1-甲基 -1H-吡唑 -4-基） 苯基） 3， 3-二甲基丁酰胺 （化合物 66) 的  N-(2,6-Dimethyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl) 3,3-dimethylbutanamide (Compound 66)
Figure imgf000069_0001
本品由 3-溴小甲基 -1H-吡唑和 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂 硼烷 -2-基）苯基） -3， 3-二甲基丁酰胺按照化合物 20D的制备方法合成， 29%收率。 MS: 300.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.18 (s， 1H), 8.09 (s， 1H), 7.82 (s， 1H), .7.26 (s， 2H), 3.96 (s， 3H), 2.21 (s， 2H), 2.15 (s， 6H)， 1.07 (s， 9H).
Figure imgf000069_0001
This product consists of 3-bromo small methyl-1H-pyrazole and N-(2,6-dimethyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxa Borane-2-yl)phenyl)-3,3-dimethylbutanamide was synthesized according to the method for the preparation of compound 20D, 29% yield. MS: 300.2 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.18 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H), .7.26 (s, 2H) , 3.96 (s, 3H), 2.21 (s, 2H), 2.15 (s, 6H), 1.07 (s, 9H).
实施例六十七  Embodiment 67
N- (4- (5， 6， 7， 8-四氢异喹啉 -3-基） 2， 6-二甲基苯） -3， 3-二甲基丁酰胺（化合物 67) 的制备
Figure imgf000069_0002
Preparation of N-(4-(5,6,7-tetrahydroisoquinolin-3-yl) 2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 67)
Figure imgf000069_0002
本品由 N- (4- (异喹啉 -3-基） 2， 6-二甲基） -3， 3-二甲基丁酰胺按照化合物 15的制备 方法，室温搅拌 2h， 25%收率。 MS: 350.8 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.19 (s, 1H) 8.32 (s, 1H), 7.75 (s, 2H), 7.63 (s, 1H), 2.74 (m， 4H)， 2.24 (s, 2H), 2.22 (s, 6H)， 1.78 (m， 4H)， 1.08 (s， 9H). This product consists of N-(4-(isoquinolin-3-yl) 2,6-dimethyl)-3,3-dimethylbutanamide according to the preparation method of compound 15 and stirred at room temperature for 2 h, 25% yield . MS: 350.8 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.19 (s, 1H) 8.32 (s, 1H), 7.75 (s, 2H), 7.63 (s, 1H), 2.74 (m, 4H), 2.24 (s, 2H), 2.22 (s, 6H), 1.78 (m, 4H), 1.08 (s, 9H).
实施例六十八  Example 68
N- (2， 6-二甲基 -4- (5， 6， 7， 8-二氢喹啉 -3-基） 苯基 -3， 3-二甲基丁酰胺盐酸盐的制 备
Figure imgf000069_0003
Preparation of N-(2,6-dimethyl-4-(5,6,6-dihydroquinolin-3-yl)phenyl-3,3-dimethylbutanamide hydrochloride
Figure imgf000069_0003
N- (2， 6-二甲基 -4- (3-喹啉基） 苯基） -3， 3-二甲基丁酰胺 （化合物 68A) 本品由 3-喹啉硼酸和 N- (4-溴 -2， 6-二甲苯基） -3， 3-二甲基丁酰胺按照化合物 19A的 制备方法合成， 48%收率。 MS: 347.2 (M+H+). N-(2,6-Dimethyl-4-(3-quinolinyl)phenyl)-3,3-dimethylbutanamide (Compound 68A) This product is synthesized from 3-quinoline boronic acid and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 19A, 48% yield. MS: 347.2 (M+H + ).
N- (2， 6-二甲基 -4- (5， 6， 7， 8-二氢喹啉 -3-基） 苯基 -3， 3-二甲基丁酰胺盐酸盐 （化 合物 68)  N-(2,6-Dimethyl-4-(5,6,8-dihydroquinolin-3-yl)phenyl-3,3-dimethylbutanamide hydrochloride (Compound 68)
本品由化合物 68A按照化合物 15的制备方法合成， 70°C搅拌过夜， 2% 收率。 MS: 351.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 8.84 (s, 1Η), 8.60 (s, 1H), 7.55 (s, 2H), 3.06-3.16 (m， 4H)， 2.38 (s， 2H), 2.36 (s， 6H)， 1.96-2.07 (m， 4H)， 1.18 (s, 9H). This product was synthesized from Compound 68A according to the preparation method of Compound 15, and stirred at 70 ° C overnight, 2% yield. MS: 351.3 (M+H+). 1H NMR (400 MHz, CD 3 OD) δ: 8.84 (s, 1 Η), 8.60 (s, 1H), 7.55 (s, 2H), 3.06-3.16 (m, 4H) , 2.38 (s, 2H), 2.36 (s, 6H), 1.96-2.07 (m, 4H), 1.18 (s, 9H).
实施例六十九  Example 69
N-(2，6-二甲基 -4-(2-喹 -3， 3-二甲基丁酰胺 （化合物 69) 的制备
Figure imgf000070_0001
本品由 2-溴喹啉和 （4- (3， 3-二甲基丁酰胺基） -3， 5-二甲苯基） 硼酸按照化合物 19A 的制备方法合成，产品用盐酸***溶液酸化得盐酸盐， 27%收率。 MS: 347.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.41 (s, 1H)， 8.73 (brs, 1H)， 8.25-8.29 (t， Ji = 8.8Hz， J2 = 6.8Hz， 2H), 8.14 (d， J = 8.0Hz, 1H)， 8.00 (s， 2H), 7.94-7.91 (t， Ji = 7.6Hz, J2 = 6.8Hz， 1H)， 7.71-7.75(t, Ji = 7.6Hz, J2 = 8 Hz, 3H), 2.31 (s， 6H)， 2.28 (s， 2H), 1.10 (s, 9H). Preparation of N-(2,6-dimethyl-4-(2-quino-3,3-dimethylbutanamide (Compound 69)
Figure imgf000070_0001
This product is synthesized from 2-bromoquinoline and (4-(3,3-dimethylbutyramido)-3,5-dimethylphenyl)boronic acid according to the preparation method of compound 19A. The product is acidified with hydrochloric acid ethyl ether solution. Acid salt, 27% yield. MS: 347.2 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.41 (s, 1H), 8.73 (brs, 1H), 8.25-8.29 (t, Ji = 8.8 Hz, J 2 = 6.8Hz, 2H), 8.14 (d, J = 8.0Hz, 1H), 8.00 (s, 2H), 7.94-7.91 (t, Ji = 7.6Hz, J 2 = 6.8Hz, 1H), 7.71-7.75(t , Ji = 7.6Hz, J 2 = 8 Hz, 3H), 2.31 (s, 6H), 2.28 (s, 2H), 1.10 (s, 9H).
实施例七十  Example seventy
N- (2， 6-二甲基 -4- (3- -3， 3-二甲基丁酰胺 （化合物 70) 的制备
Figure imgf000070_0002
Preparation of N-(2,6-dimethyl-4-(3--3,3-dimethylbutanamide (Compound 70)
Figure imgf000070_0002
本品由 3-喹啉硼酸和 N- (4-溴 -2， 6-二甲苯基） -3， 3-二甲基丁酰胺按照化合物 19A的 制备方法合成， 产品用盐酸***溶液酸化得盐酸盐， 94%收率。 MS: 347.3 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 9.56 (s, 1H), 9.23 (s, 1H), 8.27-8.30 (m， 2H), 7.80-8.04 (t， Ji = 8.4Hz， h = 8.0Hz, 1H), 7.86-7.90 (t, Ji = 7.6Hz, j2 = 8.0Hz， 1H), 7.72 (s, 2H), 2.29 (s, 6H)， 2.28 (s， 2H), 1.10 (s, 9H). This product is synthesized from 3-quinoline boronic acid and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to the preparation method of compound 19A. The product is acidified with hydrochloric acid ethyl ether solution. Acid salt, 94% yield. MS: 347.3 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 9.56 (s, 1H), 9.23 (s, 1H), 8.27-8.30 (m, 2H) ), 7.80-8.04 (t, Ji = 8.4Hz, h = 8.0Hz, 1H), 7.86-7.90 (t, Ji = 7.6Hz, j 2 = 8.0Hz, 1H), 7.72 (s, 2H), 2.29 ( s, 6H), 2.28 (s, 2H), 1.10 (s, 9H).
实施例七 ^一  Example VII ^1
N- (4- ( 1H-吲哚 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺盐酸盐的制备
Figure imgf000070_0003
叔丁基 -2- ( 4- ( 3， 3-二甲基丁酰胺基） 3， 5-二甲苯基） -1H-吲哚 -1-羧酸酯（化合物 71A) 本品由 ( 1- (叔丁基丁酰胺基) -1H-吲哚 -2-基)硼酸和 N- ( 4善 2， 6-二甲苯基) -3， 3- 二甲基丁酰胺按照化合物 19A的制备方法合成， 59%收率。 MS: 379.3 (M-56+H+). Preparation of N-(4-(1H-indol-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000070_0003
tert-Butyl-2-(4-(3,3-dimethylbutyryl)3,5-dimethylphenyl)-1H-indole-1-carboxylate (Compound 71A) (tert-Butylbutyrylamide)-1H-indol-2-yl)boronic acid and N-(4C 2,6-dimethylphenyl)-3,3-dimethylbutanamide were synthesized according to the preparation method of compound 19A , 59% yield. MS: 379.3 (M-56+H + ).
N- ( 4- ( 1H-吲哚 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺盐酸盐 (化合物 71 ) 本品由化合物 71 A按照化合物 29的制备方法合成， 53%收率。 MS: 335.3 (M+H+). 1H NMRN-(4-(1H-indol-2-yl)-2,6-xylyl)-3,3-dimethylbutyramide hydrochloride (Compound 71) This product consists of compound 71 A according to compound 29 The preparation method was synthesized, 53% yield. MS: 335.3 (M+H + ). 1H NMR
(400 MHz，CD3OD) δ: 7.56 (s， 2H), 7.53 (d， J = 8.0Hz, 1H), 7.39 (d， J = 8.0Hz, 1H), 7.08-7.10 (t，(400 MHz, CD 3 OD) δ: 7.56 (s, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.08-7.10 (t,
1H), 7.00-7.02 (t， 1H), 6.79 (s， 1H), 2.36 (s， 2H), 2.32 (s， 6H)， 1.18 (s, 9H). 1H), 7.00-7.02 (t, 1H), 6.79 (s, 1H), 2.36 (s, 2H), 2.32 (s, 6H), 1.18 (s, 9H).
实施例七十二  Example seventy two
N- ( 2， 6-二甲基 -4- (吡啶小基甲苯） 苯基） -3， 3-二甲丁酰胺盐酸盐 （化合物 72 ) 的制
Figure imgf000071_0001
Preparation of N-(2,6-dimethyl-4-(pyridine)toluene)phenyl)-3,3-dimethylbutyramide hydrochloride (Compound 72)
Figure imgf000071_0001
4- ( 3,3-二甲基叔丁酰胺） -3,5-二甲基苯甲醇磺酸酯（100 mg， 0.31 mmol)，碳酸钾（129.3 mg， 0.93 mmol) 和哌啶 （38 M/， 0.40 mmol) 溶于乙腈中， 50°C搅拌反应 2小时。 反应液旋 干除掉乙腈， 加入水， 用乙酸乙酯提取， 合并有机层， 用无水硫酸钠干燥， 旋干。 粗品经过 柱色谱提纯 （石油醚 /乙酸乙酯 =1 : 1 ) 得到固体化合物， 该化合物使用盐酸***溶液酸化后 得到化合物 72， 为白色固体 （80 mg， 82%产率） 。 MS: 317.5 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 10.00 (brs, 1Η), 9.28 (s, 1H), 7.26 (s, 2H), 4.15 (d, J = 5.2 Hz, 2H), 3.41 (brs, 4H)， 3.29 (m， 2H), 2.85 (m， 2H), 2.24 (s， 2H), 2.17 (s， 6H)， 1.37 (m， 2H), 1.07 (s， 9H). 4-(3,3-dimethyl-tert-butyramide)-3,5-dimethylbenzyl alcohol sulfonate (100 mg, 0.31 mmol), potassium carbonate (129.3 mg, 0.93 mmol) and piperidine (38 M /, 0.40 mmol) Dissolved in acetonitrile and stirred at 50 ° C for 2 hours. The reaction mixture was evaporated to dryness EtOAc. The crude product was purified by EtOAc EtOAcjjjjjjjj MS: 317.5 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 10.00 (brs, 1 Η), 9.28 (s, 1H), 7.26 (s, 2H), 4.15 (d, J = 5.2 Hz, 2H), 3.41 (brs, 4H), 3.29 (m, 2H), 2.85 (m, 2H), 2.24 (s, 2H), 2.17 (s, 6H), 1.37 (m, 2H), 1.07 (s , 9H).
实施例七十三  Example seventy three
N- ( 4- ( ( 3-二氢异喹啉 -1 ( 2H) -基） -甲基） -2， 6-二甲基） -3， 3-二甲基丁酰胺盐酸 盐的制备
Figure imgf000071_0002
Preparation of N-(4-((3-dihydroisoquinolin-1(2H)-yl)-methyl)-2,6-dimethyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000071_0002
4- ( 3,3-二甲基叔丁酰胺） -3,5-二甲基苯甲醇磺酸酯 （化合物 73A)  4-(3,3-dimethyl-tert-butyramide)-3,5-dimethylbenzyl alcohol sulfonate (Compound 73A)
N， N-二异丙基乙胺 ( DIEA, 227 mg, 1.72 mmol) 在 0 °C加入到 N- ( 4- (羟甲基) -2 , 6-二甲基苯） -3， 3-二甲基丁酰胺 （220 mg， 0.88 mmol ) 乙腈溶液中， 0 °C搅拌 10分钟， 甲 基磺酰氯 （181 M/， 1.06 mmol) 溶于 5 ml乙腈中， 在 0 °C滴加入反应液中， 室温搅拌反应 1 小时。 反应液旋干， 用碳酸氢钠溶液洗涤， 乙酸乙酯提取， 提取层用无水硫酸钠干燥， 浓縮。 所得到的产物粗品直接用于下一步反应 （220 mg，76%收率） 。 N- (4- ( ( 3-二氢异喹啉 -1 (2H) -基） -甲基） -2， 6-二甲基） -3， 3-二甲基丁酰胺盐酸 盐 （化合物 73 ) N, N-Diisopropylethylamine (DIEA, 227 mg, 1.72 mmol) was added to N-(4-(hydroxymethyl)-2,6-dimethylphenyl)-3, 3- at 0 °C Methyl butyl amide (220 mg, 0.88 mmol) in acetonitrile solution, stirring at 0 ° C for 10 minutes, methanesulfonyl chloride (181 M /, 1.06 mmol) dissolved in 5 ml of acetonitrile, and added to the reaction solution at 0 ° C The reaction was stirred at room temperature for 1 hour. The reaction mixture was dried with EtOAc EtOAc m. The crude product obtained was used directly in the next step (220 mg, 76% yield). N-(4-((3-Dihydroisoquinolin-1(2H)-yl)-methyl)-2,6-dimethyl)-3,3-dimethylbutanamide hydrochloride (compound) 73)
本品由化合物 73A和四氢异喹啉按照化合物 72的制备方法合成， 37%收率。 MS: 365.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.10 (brs, 1Η), 6.95 (s, 1H), 6.91 (m， 1H), 6.47 (brs, 2H), 4.39 (s， 2H), 3.36 (t，J= 6.0 Hz, 2H), 2.74 (t，J= 6.0 Hz, 2H), 2.20 (s， 2H), 2.11 (s， 6H)， 1.93 (m， 2H), 1.06 (s， 9H).  This product was synthesized from Compound 73A and tetrahydroisoquinoline according to the preparation method of Compound 72, yield 37%. MS: 365.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.10 (brs, 1 Η), 6.95 (s, 1H), 6.91 (m, 1H), 6.47 (brs, 2H), 4.39 (s, 2H), 3.36 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.20 (s, 2H), 2.11 (s, 6H), 1.93 (m, 2H) , 1.06 (s, 9H).
实施例七十四  Example seventy four
N-(4-((3，4-二氢异喹啉 -2(1H)-基)甲基) -2，6-二甲基 )-3， 3-二甲基丁酰胺 （化合物 74) 的制 备
Figure imgf000072_0001
N-(4-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-2,6-dimethyl)-3,3-dimethylbutanamide (Compound 74) Preparation
Figure imgf000072_0001
四氢异喹啉和 N-(4-甲酰基 -2,6-二甲苯基) -3,3-二甲基丁酰胺加入到 1，2-二氯乙浣，在 0°C加 入三乙酰氧基硼氢化钠， 在 25 °C反应 2 小时， 用氯化铵溶液终止反应， 乙酸乙酯萃取 （20 mLx3), 无水硫酸钠干燥， 减压旋干， 柱层析得到化合物 74为白色固体 （50 mg， 收率 29%)。 MS: 363 (M-H+). 1H NMR (CDC13, 400 MHz): δ 7.08-7.15 (m， 5H)， 6.98-7.01 (m， 1H), 6.59 (s, 1H)， 3.62 (d, J= 14 Hz, 4H)， 2.90 (s, 2H), 2.75 (s, 2H), 2.30 (s, 2H), 2.24 (s, 6H)， 1.15 (s, 9H). 实施例七十五 Tetrahydroisoquinoline and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutyramide were added to 1,2-dichloroacetamidine, and triacetyl was added at 0 °C. Sodium oxyborohydride, which was reacted at 25 ° C for 2 hours, quenched with ammonium chloride solution, extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate. Solid (50 mg, yield 29%). MS: 363 (M-H+). 1H NMR (CDC1 3 , 400 MHz): δ 7.08-7.15 (m, 5H), 6.98-7.01 (m, 1H), 6.59 (s, 1H), 3.62 (d, J = 14 Hz, 4H), 2.90 (s, 2H), 2.75 (s, 2H), 2.30 (s, 2H), 2.24 (s, 6H), 1.15 (s, 9H). Example 75
N-(4-((3，4-二氢 - 1，4-亚甲基异喹啉 -2( 1 H)-¾)甲基) -2,6-二甲基苯基 )-3，3-二甲基丁酰胺（化 合物 75 ) 的制备
Figure imgf000072_0002
N-(4-((3,4-Dihydro-1,4-methyleneisoquinolin-2(1H)-3⁄4)methyl)-2,6-dimethylphenyl)-3, Preparation of 3-dimethylbutyramide (Compound 75)
Figure imgf000072_0002
本品由 1，2，3，4-四氢 -1,4-亚甲基异喹啉和 N-(4-甲酰基 -2,6-二甲苯基) -3,3-二甲基丁酰胺按 照化合物 74的制备方法合成， 12%收率。 MS: 377 (M+H+).1H NMR (OMSO-d6, 400 MHz): δ 9.05 (s, 1H), 7.34-7.31 (m， 1H), 7.20-7.17 (m， 3H), 6.94 (s, 2H), 4.15 (s, 1H), 3.44 (s, 1H), 3.33 (d, J=8.0 Hz, 2H), 2.66 (d, J=10.4 Hz, 2H), 2.20 (s, 2H), 2.11 (s, 6H)， 1.95 (d, J=6.0 Hz, 1H), 1.68 (d, J=6.0 Hz, 1H), 1.40-1.38 (m, 1H), 1.06 (s, 9H). This product consists of 1,2,3,4-tetrahydro-1,4-methylene isoquinoline and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutyl The amide was synthesized according to the method for the preparation of compound 74 in 12% yield. MS: 377 (M+H + ).1H NMR (OMSO-d6, 400 MHz): δ 9.05 (s, 1H), 7.34-7.31 (m, 1H), 7.20-7.17 (m, 3H), 6.94 (s , 2H), 4.15 (s, 1H), 3.44 (s, 1H), 3.33 (d, J=8.0 Hz, 2H), 2.66 (d, J=10.4 Hz, 2H), 2.20 (s, 2H), 2.11 (s, 6H), 1.95 (d, J=6.0 Hz, 1H), 1.68 (d, J=6.0 Hz, 1H), 1.40-1.38 (m, 1H), 1.06 (s, 9H).
实施例七十六  Example seventy six
N-(4- (引哚啉小基甲基) -2，6-二甲基苯基) -3，3-二甲基 （化合物 76) 的制备
Figure imgf000072_0003
二氢吲哚 (62 mg， 0.53 mmol)和 N-(4-甲酰基 -2，6-二甲基苯基) -3，3-二甲基丁酰胺 (123 mg， 0.5 mmol)溶解在 15m 1，2-二氯乙烷中，在 25°C时向此溶液中加入 0.05ml三氟乙酸。然后在室 温下搅拌 20分钟， 再加入氰基硼氢化钠 (251 mg， 4mmol), 此后再在室温下搅拌 2小时。 反应 结束后， 用饱和氯化铵溶液终止， 乙酸乙酯萃取 （3 X 20 mL) ， 合并有机相， 用饱和食盐水 洗， 用无水硫酸钠干燥两个小时， 过滤， 乙酸乙酯 /石油醚 （1 :3 )过柱分离得到化合物 76 (70 mg， 40%收率）。 1H NMR (CDC13, 400 MHz): δ 7.11-7.05 (m， 4H)， 6.71-6.66 (m， 1H), 6.58 (brs, 1H), 6.58-6.52 (m， 1H), 4.16 (s， 2H), 3.31 (t，J= 8.3, 2H), 2.97 (t，J= 8.3, 2H), 2.30 (s， 2H), 2.23 (s， 6H)， 1.16 (s, 9H). MS: 351 (M+H+). Preparation of N-(4-(pyridinium phenylmethyl)-2,6-dimethylphenyl)-3,3-dimethyl (Compound 76)
Figure imgf000072_0003
Indoline (62 mg, 0.53 mmol) and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutanamide (123 mg, 0.5 mmol) dissolved in 15 m To 1,2-dichloroethane, 0.05 ml of trifluoroacetic acid was added to the solution at 25 °C. After stirring at room temperature for 20 minutes, sodium cyanoborohydride (251 mg, 4 mmol) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, it was quenched with EtOAc EtOAc (EtOAc) (1:3) Column separation gave compound 76 (70 mg, 40% yield). 1H NMR (CDC1 3 , 400 MHz): δ 7.11-7.05 (m, 4H), 6.71-6.66 (m, 1H), 6.58 (brs, 1H), 6.58-6.52 (m, 1H), 4.16 (s, 2H ), 3.31 (t, J = 8.3, 2H), 2.97 (t, J = 8.3, 2H), 2.30 (s, 2H), 2.23 (s, 6H), 1.16 (s, 9H). MS: 351 (M +H + ).
实施例七十七  Example seventy seven
N-(4-((6，7-二氢噻吩 [3，2-C]吡啶 -5(4H)-基)甲基) -2，6-二甲基本苯基 )-3，3-二甲基丁酰胺
Figure imgf000073_0001
N-(4-((6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)methyl)-2,6-dimethylphenyl)-3,3-di Methylbutyramide
Figure imgf000073_0001
N-(4-甲酰基 -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 77A)  N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 77A)
在氮气的保护下， 将 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺 (3 g， 10.1 mmol) 溶于干燥的四氢呋喃（50 ml)后，冷却至 -78 °C，滴加正丁基锂的正己烷溶液 (8.8 ml, 14.1 mmol, 1.6 mol/L)，并保持温度稳定在 -78 搅拌一个小时， 然后加入 DMF ( 1.4 ml, 18 mmol) 。 该反 应液在 -78 °0搅拌一个小时， 反应结束后， 加入饱和的氯化铵溶液， 乙酸乙酯萃取， 无水硫 酸钠干燥， 过滤， 滤液旋干， 柱色谱分离， 用石油醚： 乙酸乙酯 =4:1纯化得到化合物 77A (1.2 g，48%收率） 。 MS: 248 (M+H+).  N-(4-Bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (3 g, 10.1 mmol) was dissolved in dry tetrahydrofuran (50 ml) under nitrogen. After cooling to -78 °C, add n-hexane solution of n-butyllithium (8.8 ml, 14.1 mmol, 1.6 mol/L), keep the temperature stable at -78 and stir for one hour, then add DMF (1.4 ml). , 18 mmol). The reaction mixture was stirred at -78 °C for one hour. After completion of the reaction, a saturated ammonium chloride solution was added, ethyl acetate was evaporated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. Ethyl ester = 4:1 was purified to afford compound 77A (1. g, 48% yield). MS: 248 (M+H+).
N-(4-((6，7-二氢噻吩 [3，2-C]吡啶 -5(4H)-基)甲基) -2,6-二甲基本苯基 )-3，3-二甲基丁酰胺 （化 合物 77) N-(4-((6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)methyl)-2,6-dimethylphenyl)-3,3-di Methylbutyramide (Compound 77)
本品由 4，5，6，7-四氢噻吩 [3，2-C]吡啶和化合物 77A按照化合物 74的制备方法合成， 35%收 率。 1H NMR (CDC13, 400 MHz): 5 7.11 (s, 2H), 7.07 (d, J= 5.1 Hz 1H), 6.70 (d，J= 5.1 Hz 1H)， 6.60 (brs, 1H), 3.62 (s， 2H) 3.56 (s， 2H), 2.88 (t， J= 5.3 Hz, 2H), 2.80 (t， J= 5.3 Hz, 2H)， 2.30 (s， 2H), 2.25 (s， 6H)， 1.15 ， 9H). MS: 371 (M+H+). This product was synthesized from 4,5,6,7-tetrahydrothiophene [3,2- C ]pyridine and compound 77A according to the preparation method of compound 74 in a yield of 35%. 1H NMR (CDC1 3 , 400 MHz): 5 7.11 (s, 2H), 7.07 (d, J = 5.1 Hz 1H), 6.70 (d, J = 5.1 Hz 1H), 6.60 (brs, 1H), 3.62 (s , 2H) 3.56 (s, 2H), 2.88 (t, J = 5.3 Hz, 2H), 2.80 (t, J = 5.3 Hz, 2H), 2.30 (s, 2H), 2.25 (s, 6H), 1.15, 9H). MS: 371 (M+H + ).
实施例七十八  Example seventy eight
N-(4-((4，5-二氢噻吩并 [2，3-c]吡啶 -6(7H)-基)甲基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺 （化 合物 78) 的制备
Figure imgf000073_0002
本品由 4，5，6，7-四氢噻吩并 [2，3-c]吡啶和 N-(4-甲酰基 -2，6-二甲基苯基) -3，3-二甲基丁酰胺 按照化合物 74的制备方法合成， 25°C反应 12小时， 43%收率。 1H NMR (DMSO, 400 MHz): δ 9,08 (brs, 1H), 7.28 (d, J= 5.2 Hz 1H), 7.03 (s, 2H), 6.82 (d, J= 5.2 Hz 1H), 3.57 (d, J= 6.0 Hz 4H)， 2.69 (m， 2H), 2.64 (m， 2H), 2.21 (s， 2H), 2.13 (s， 6H)， 1.06 (s， 9H). MS: 371.3 (M+H+). N-(4-((4,5-Dihydrothieno[2,3-c]pyridine-6(7H)-yl)methyl)-2,6-dimethylphenyl)-3,3- Preparation of dimethylbutyramide (compound 78)
Figure imgf000073_0002
This product consists of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethyl Butanamide was synthesized according to the preparation method of Compound 74, and reacted at 25 ° C for 12 hours, 43% yield. 1H NMR (DMSO, 400 MHz): δ 9,08 (brs, 1H), 7.28 (d, J = 5.2 Hz 1H), 7.03 (s, 2H), 6.82 (d, J = 5.2 Hz 1H), 3.57 ( d, J = 6.0 Hz 4H), 2.69 (m, 2H), 2.64 (m, 2H), 2.21 (s, 2H), 2.13 (s, 6H), 1.06 (s, 9H). MS: 371.3 (M+ H + ).
实施例七十九  Example seventy nine
N- (4 ( (2，3-二氢 -1H-吡咯 [2，3-b]吡啶） 甲基） -2，6-二甲基苯基） -3，3-二甲基丁酰胺的制 备
Figure imgf000074_0001
N-(4 ((2,3-Dihydro-1H-pyrrole[2,3-b]pyridine)methyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide preparation
Figure imgf000074_0001
4- (3,3-二甲基丁酰胺） -3-甲基苯甲醛 （化合物 79A)  4-(3,3-dimethylbutyramide)-3-methylbenzaldehyde (Compound 79A)
在 -78°C和 N2的保护下， 向 N-(4-溴 -2， 6-二甲基苯基) -3,3-二甲基丁酰胺 (3 g， 10.1 mmol) 的四氢呋喃 (50 ml)溶液中慢慢的滴加正丁基锂 (8.8 ml, 14.1 mmol, 1.6 mol/L 的正己烷溶液)。 将此反应在 -78°C下搅拌 1小时后，再向此混合液中滴加 N，N-二甲基甲酰胺 (1.4 ml, 18 mmol), 继续反应一小时， 用饱和氯化铵溶液终止， 乙酸乙酯萃取， 有机相用无水硫酸钠干燥， 减压 旋干溶剂，过柱得到产物 C1.2 g， 48% 收率). MS: 248 (M+H+). To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (3 g, 10.1 mmol) in tetrahydrofuran under -78 ° C and N 2 ( 50 ml of the solution was slowly added dropwise n-butyllithium (8.8 ml, 14.1 mmol, 1.6 mol/L in n-hexane). After the reaction was stirred at -78 ° C for 1 hour, N,N-dimethylformamide (1.4 ml, 18 mmol) was added dropwise to the mixture, and the reaction was continued for one hour with a saturated ammonium chloride solution. terminated, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure, to give the product by column C1.2 g, 48% yield) MS:. 248 (M + H +).
N- (4- (氢氧基甲基） -2， 6-二甲基苯基） -3,3-二甲基丁酰胺 (化合物 79B)  N-(4-(Hydroxymethyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 79B)
在 0°C下，向化合物 79A (130 mg, 0.53 mmol)的甲醇溶液 (；50 ml)中慢慢的加入硼氢化钠 (；22 mg, 0.58 mmol) 将此反应升到室温搅拌 1小时后， 用饱和氯化铵溶液终止， 乙酸乙酯萃取， 有机相用无水硫酸钠干燥， 减压旋干溶剂，过柱得到化合物 79B (110 mg， 83% 收率)。 MS: 250 (M+H+).  To a solution of compound 79A (130 mg, 0.53 mmol) in methanol (50 ml) was slowly added sodium borohydride (22 mg, 0.58 mmol) at 0 ° C. The mixture was quenched with EtOAc (EtOAc)EtOAc. MS: 250 (M+H+).
N- (4- (氯甲基） -2， 6-二甲基苯基） -3,3-二甲基丁酰胺 （化合物 79C)  N-(4-(Chloromethyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 79C)
化合物 79B(110 mg, 0.44 mmol)的氯化亚砜 (2 ml)溶液回流二小时， 用饱和碳酸氢钠溶液 终止，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压旋干溶剂，过柱得到化合物 79C (100 mg, A solution of the compound 79B (110 mg, 0.44 mmol) eluted eluted eluted eluted eluted eluted , through the column to get the compound 79C (100 mg,
85% 收率）。 85% yield).
N- (4 ( (2,3-二氢 -1H-吡咯 [2，3-b]吡啶） 甲基） -2,6-二甲基苯基） -3,3-二甲基丁酰胺 （化 合物 79)  N-(4 ((2,3-Dihydro-1H-pyrrole[2,3-b]pyridine)methyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide Compound 79)
将化合物 79C (100 mg, 0.37 mmol)和碳酸氢钠的水溶液加热到 90°C， 然后加入 2，3-二氢 -111-吡咯[2，3-1)]吡啶(；43 1¾，0.36 1^^1)， 继续加热到 95°C搅拌 8小时， 加入 10ml甲苯， 并使 反应保持在 60-80°C 5分钟。 冷却到室温， 分离有机层， 用无水硫酸钠干燥， 减压旋干溶剂， 过柱得到化合物 79 (50 mg, 38% 收率）。 1H NMR (CDC13， 400 MHz): δ 7.85-7.83 (m， 1H)， 7.24-7.19 (m， 1H)， 7.04 (s， 2H)， 6.62 (brs, 1H)， 6.46-6.44 (m， 1H)， 4.92 (s， 2H)， 3.38 (t， J = 8 Hz, 2H), 2.95 (t， J= 8 Hz, 2H), 2.29 (s， 2H), 2.22 (s， 6H)， 1.15 (s, 9H) MS: 352 (M+H+). An aqueous solution of compound 79C (100 mg, 0.37 mmol) and sodium hydrogencarbonate was heated to 90 ° C, then 2,3-dihydro-111-pyrrole[2,3-1)]pyridine (43 13⁄4, 0.36 1) was added. ^^1), heating was continued to 95 ° C for 8 hours, 10 ml of toluene was added, and the reaction was maintained at 60-80 ° C for 5 minutes. After cooling to room temperature, the organic layer was separated, dried over anhydrous sodium sulfate. 1H NMR (CDC1 3 , 400 MHz): δ 7.85-7.83 (m, 1H), 7.24-7.19 (m, 1H), 7.04 (s, 2H), 6.62 (brs, 1H), 6.46-6.44 (m, 1H), 4.92 (s, 2H), 3.38 (t, J = 8 Hz, 2H) , 2.95 (t, J= 8 Hz, 2H), 2.29 (s, 2H), 2.22 (s, 6H), 1.15 (s, 9H) MS: 352 (M+H + ).
实施例八十  Example eighty
N-(2，6-二甲基 -4-C3-氮杂螺 [5.5]十一烷 -3-基)苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000075_0001
Preparation of N-(2,6-dimethyl-4-C3-azaspiro[5.5]undec-3-yl)phenyl)-3,3-dimethylbutanamide
Figure imgf000075_0001
3-氮杂螺 [5.5] ^—烷 （化合物 80A)  3-Azaspiro[5.5]^-alkane (Compound 80A)
本品由 3-氮杂 -[5，5]-壬烷 -2,4-二酮按照化合物 5G的制备方法合成， 71% 收率。 MS: 154 (M+H+).  This product was synthesized from 3-aza-[5,5]-nonane-2,4-dione according to the preparation method of compound 5G, yield 71%. MS: 154 (M+H+).
3-(3，5-二甲基 -4-硝基苯基) -3-氮杂螺 [5.5]十一烷 （化合物 80B)  3-(3,5-Dimethyl-4-nitrophenyl)-3-azaspiro [5.5]undecane (Compound 80B)
本品由化合物 80A和 4-氟 -2,3-二甲基硝基苯按照化合物 53A的制备方法合成， 34%收率。 2，6-二甲基 -4-(3-氮杂螺 [5.5]十一烷 -3-基)苯胺 （化合物 80C)  This product was synthesized from Compound 80A and 4-fluoro-2,3-dimethylnitrobenzene according to the preparation method of Compound 53A, yield of 34%. 2,6-Dimethyl-4-(3-azaspiro[5.5]undecyl-3-yl)aniline (Compound 80C)
室温下， 化合物 80B (195 mg， 0.65 mmol)和钯碳催化剂 （19.5 mg， 10%)二氯甲烷 (10ml)禾口 甲醇 (15ml)的混合溶液搅拌 1.5小时。 反应结束后， 过滤， 旋干得到化合物 80C(158 mg， 90%收 率)。  A mixed solution of the compound 80B (195 mg, 0.65 mmol) and palladium-carbon catalyst (19.5 mg, 10%) dichloromethane (10 ml) and methanol (15 ml) was stirred at room temperature for 1.5 hours. After completion of the reaction, filtration and spin-drying gave Compound 80C (158 mg, 90% yield).
N-(2，6-二甲基 -4-(3-氮杂螺 [5.5]十一烷 -3-基)苯基) -3,3-二甲基丁酰胺 （化合物 80)  N-(2,6-Dimethyl-4-(3-azaspiro[5.5]undec-3-yl)phenyl)-3,3-dimethylbutanamide (Compound 80)
0°C下， 在化合物 80C (125 mg， 0.46 mmol)和三乙胺 (0.077 ml, 0.55 mmol)二氯甲烷的溶液 中加入 3，3-二甲基丁酰氯 (92 mg， 0.69 mmol), 然后在室温下反应 0.5小时。反应结束后， 用饱 和碳酸钠溶液终止反应， 乙酸乙酯萃取 （3 X 20 mL) ， 合并有机相， 用饱和食盐水洗， 用无 水硫酸钠干燥，过滤，旋干过柱得到化合物 80 (137mg, 81% 收率)。 1HNMR (CDC13, 400 MHz): 6.78 (s, 1H), 6.72 (s, 1H), 6.52 (brs, 1H), 2,27 (s, 2H), 2.21 (s, 6H)， 1.57-1.25 (m， 18H), 1.15 (s, 9H). MS: 371 (M+H+). 3,3-Dimethylbutyryl chloride (92 mg, 0.69 mmol) was added to a solution of compound 80C (125 mg, 0.46 mmol) and triethylamine (0.077 ml, 0.55 mmol) dichloromethane. It was then reacted at room temperature for 0.5 hours. After completion of the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. , 81% yield). 1HNMR (CDC1 3 , 400 MHz): 6.78 (s, 1H), 6.72 (s, 1H), 6.52 (brs, 1H), 2,27 (s, 2H), 2.21 (s, 6H), 1.57-1.25 ( m, 18H), 1.15 (s, 9H). MS: 371 (M+H+).
实施例八十一  Example eighty one
N-(2，6-二 -4-(8-氮螺 [4.5] 癸烷 -8-基)苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000075_0002
Preparation of N-(2,6-di-4-(8-azaspiro[4.5]decane-8-yl)phenyl)-3,3-dimethylbutanamide
Figure imgf000075_0002
8-氮杂螺 [4.5] 癸烷 （化合物 81A)  8-Azaspiro [4.5] decane (Compound 81A)
本品由 8-氮杂螺 〔4，5〕 癸烷 -7,9-二酮按照化合物 5G的制备方法合成， 95%收率 < 8-(3， 5-二甲基 -4-硝基苯基) -8-氮螺 [4.5] 癸烷 （化合物 81B) 本品由化合物 81A和 4-氟 -2,3-二甲基硝基苯按照化合物 53A的制备方法合成， 120°C反 应 24h， 59%收率。 This product is synthesized from 8-azaspiro[4,5]nonane-7,9-dione according to the preparation method of compound 5G, 95% yield < 8-(3, 5-dimethyl-4-nitro Phenyl)-8-azaspiro[4.5]decane (compound 81B) This product was synthesized from compound 81A and 4-fluoro-2,3-dimethylnitrobenzene according to the preparation method of compound 53A, and reacted at 120 ° C for 24 h, 59% yield.
2，6-二甲基 -4-(8-氮螺 [4.5] 癸烷 -8-基)胺 （化合物 81C)  2,6-Dimethyl-4-(8-azaspiro[4.5]decane-8-yl)amine (Compound 81C)
本品由化合物 81B按照化合物 80C的制备方法， 室温反应 12h， 89%收率。  This product was reacted with compound 81B according to the preparation method of compound 80C at room temperature for 12 h, 89% yield.
N-(2，6-二甲基 -4-(8-氮螺 [4.5] 癸烷 -8-基)苯基) -3,3-二甲基丁酰胺 （化合物 81 )  N-(2,6-Dimethyl-4-(8-azaspiro[4.5]decane-8-yl)phenyl)-3,3-dimethylbutanamide (Compound 81)
本品由化合物 81C和 3，3-二甲基丁酰氯按照化合物 80的制备方法合成， 78%收率。 MS: 357.3 (M+H+).1H NMR (400 MHz, CDC13) δ: 6.67 (d, J= 6.4 Hz, 1H), 6.56 (s， 1H), 3.14 (t, J= 6.5 Hz, 2H), 2.27 (s, 2H), 2.21 (s, 6H)， 1.67-1.60(m, 8H)， 1.58-1.45(m, 4H)， 1.04 (s, 9H). This product was synthesized from the compound 81C and 3,3-dimethylbutyryl chloride according to the preparation method of the compound 80, 78% yield. MS: 357.3 (M+H+).1H NMR (400 MHz, CDC1 3 ) δ: 6.67 (d, J = 6.4 Hz, 1H), 6.56 (s, 1H), 3.14 (t, J = 6.5 Hz, 2H) , 2.27 (s, 2H), 2.21 (s, 6H), 1.67-1.60 (m, 8H), 1.58-1.45 (m, 4H), 1.04 (s, 9H).
实施例八十二  Example eighty two
N 2，4-二甲基 -6-(8-氮螺 [4.5]葵烷 -8-基)吡啶 -3-基) -3，3 -二甲基丁酰胺的制备
Figure imgf000076_0001
Preparation of N 2,4-dimethyl-6-(8-azaspiro[4.5] oxane-8-yl)pyridin-3-yl)-3,3-dimethylbutanamide
Figure imgf000076_0001
8-氮螺 [4,5]葵烷 （化合物 82A)  8-azaspiro [4,5] alkane (compound 82A)
本品由 8-氮螺 [4.5] 癸烷 -7,9-二酮按照化合物 5G的制备方法合成， 收率 90%。 MS: 140 [M+H]+. This product is synthesized from 8-aziro[4.5]decane-7,9-dione according to the preparation method of compound 5G, and the yield is 90%. MS: 140 [M+H] + .
8- (4,6-二甲基 -5-硝基吡啶 -2-基） -8 -氮螺 [4.5]葵烷 （化合物 82B )  8-(4,6-Dimethyl-5-nitropyridin-2-yl)-8-azaspiro [4.5] Alkane (Compound 82B)
本品由化合物 82A和 6-氯 -2,4-二甲基 -3-硝基吡啶按照 53A的制备方法合成， 100% 收率。 MS: 290 [M+H]+.  This product was synthesized from Compound 82A and 6-chloro-2,4-dimethyl-3-nitropyridine according to the preparation method of 53A in 100% yield. MS: 290 [M+H]+.
2，4-二甲基 -6- ( 8-氮螺 [4.5]葵烷 -8-基） 吡啶 -3-胺 （化合物 82C)  2,4-Dimethyl-6-(8-azaspiro[4.5]ol-8-yl)pyridine-3-amine (Compound 82C)
本品由化合物 82B按照化合物 1C的制备方法， 封管 90°C反应 16h， 98%收率。 MS: 260 [M+H]+. This product is prepared from compound 82B according to the preparation method of compound 1C, and sealed at 90 ° C for 16 h, 98% yield. MS: 260 [M+H] + .
N- (2,4-二甲基 -6- ( 8-氮螺 [4.5]葵烷 -8-基） -吡啶 -3-基） -3,3 -二甲基丁酰胺 （化合物 82) 本品由化合物 82C按照化合物 2的制备方法合成， 54%收率。 MS: 358 [M+H]+. 1HNMRN-(2,4-Dimethyl-6-(8-azaspiro[4.5]-ol-8-yl)-pyridin-3-yl)-3,3-dimethylbutanamide (Compound 82) The product was synthesized from Compound 82C according to the method for the preparation of Compound 2, yield 54%. MS: 358 [M+H] + . 1HNMR
(CDCls 400MHz): 6.58 (s, 1H), 6.38(s, 1H), 3.55-3.48 (m, 4H), 2.34(s, 3H), 2.28(s, 2H), 2.17 (s,(CDCls 400MHz): 6.58 (s, 1H), 6.38(s, 1H), 3.55-3.48 (m, 4H), 2.34(s, 3H), 2.28(s, 2H), 2.17 (s,
3H), 1.69-1.62 (m， 4H)， 1.58-1.46 (m， 8H)， 1.16 (s， 9H). 3H), 1.69-1.62 (m, 4H), 1.58-1.46 (m, 8H), 1.16 (s, 9H).
实施例八十三  Example eighty three
N-(2 6-二甲基 -4- ( 6-氮杂螺 [2.5]辛烷基） 苯基) -3,3-二甲基丁酰胺的制备
Figure imgf000076_0002
N-Cbz-4-甲叉基哌啶 （化合物 83A) Preparation of N-(2 6-dimethyl-4-( 6-azaspiro[2.5]octyl)phenyl)-3,3-dimethylbutanamide
Figure imgf000076_0002
N-Cbz-4-methylidene piperidine (compound 83A)
冰水浴下， 叔丁醇钾 （2.2 g， 19.3 mmol) 的四氢呋喃 （30 mL) 溶液缓慢滴加到甲基三 苯基溴化膦 （6.9 g， 19.3 mmol) 的四氢呋喃 （30 mL) 悬浊液中， 30分钟后升至室温继续搅 拌 30分钟。 在冰水浴冷却下， 滴加 N-Cbz-4-哌啶酮 （3g， 12.9 mmol) 的四氢呋喃 （30 mL) 溶液， 自然升至室温， 继续搅拌 12小时。 真空旋干溶剂， 用水稀释残渣， 乙酸乙酯和石油醚 A solution of potassium tert-butoxide (2.2 g, 19.3 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise to a solution of methyltriphenylphosphonium bromide (6.9 g, 19.3 mmol) in tetrahydrofuran (30 mL). After 30 minutes, the temperature was raised to room temperature and stirring was continued for 30 minutes. A solution of N-Cbz-4-piperidone (3 g, 12.9 mmol) in tetrahydrofuran (30 mL) was then evaporated. Dry the solvent in vacuo, dilute the residue with water, ethyl acetate and petroleum ether
(1： 1， 2x50 mL) 萃取， 合并有机相， 用饱和食盐水洗涤， 无水硫酸钠干燥， 真空浓縮， 柱层析 （石油醚： 酸乙酯 =32: 1) 得到化合物 83A (2.4 g， 收率 80%) 。 (1:1, 2x50 mL), EtOAc (EtOAc: EtOAc (EtOAc) g, yield 80%).
N-Cbz-6-氮杂螺 [2.5]辛烷 （化合物 83B)  N-Cbz-6-azaspiro[2.5]octane (compound 83B)
冰水浴下， 三氟乙酸 （0.55 mL， 8.6 mmol) 的二氯甲烷 （10mL) 溶液滴加到二乙基锌 (8.6 mL, 1 M正己烷溶液， 8.6 mmol) 的四氢呋喃 （lOOmL) 溶液中， 继续搅拌 30分钟。 滴加二碘甲烷 （0.7 mL， 8.6 mmol) 的二氯甲烷 （5mL) 溶液到该反应体系中， 并继续搅拌 30分钟。 滴加化合物 83A (l g， 4.3 mmol) 的二氯甲烷 （5mL)溶液到该反应体系中， 升至 室温继续搅拌 18小时 （至 LC-MS显示反应完全为止） 。 加入 20 mL二氯甲烷稀释， 倾倒入 30 mL饱和碳酸氢钠溶液中， 过滤除去不溶物， 固体用 50 mL二氯甲烷洗涤。 分离有机相， 并用饱和食盐水洗涤， 无水硫酸钠干燥， 过滤， 真空旋干， 柱层析 （石油醚： 酸乙酯 =25: 1) 得到化合物 83B (0.83 g， 收率 81%) 。  Under ice water bath, a solution of trifluoroacetic acid (0.55 mL, 8.6 mmol) in dichloromethane (10 mL) was added dropwise to diethylzinc (8.6 mL, 1 M hexane solution, 8.6 mmol) in tetrahydrofuran (100 mL). Stirring was continued for 30 minutes. A solution of diiodomethane (0.7 mL, 8.6 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture and stirring was continued for 30 min. A solution of compound 83A (1 g, 4.3 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture and the mixture was warmed to room temperature and stirred for 18 hours (to LC-MS, the reaction was completed). Diluted with 20 mL of dichloromethane, poured into 30 mL of saturated sodium bicarbonate solution, filtered to remove insoluble material, and the solid was washed with 50 mL of dichloromethane. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
6-氮杂螺 [2.5]辛烷氢溴酸盐 （化合物 83C)  6-azaspiro[2.5]octane hydrobromide (compound 83C)
冰水浴下， 氢溴酸 （3mL， 33%的醋酸溶液） 滴加到化合物 83B (0.4 g， 1.7 mmol) 的 醋酸（3mL)溶液中。 室温搅拌 15小时。 LCMS显示反应完全后， 真空旋干溶剂， 得到化合 物 83C (0.32 g, 收率 100%) 。  Under ice-water bath, hydrobromic acid (3 mL, 33% acetic acid) was added dropwise to a solution of compound 83B (0.4 g, 1.7 mmol) in acetic acid (3 mL). Stir at room temperature for 15 hours. After LCMS showed the reaction was completed, the solvent was evaporated in vacuo to give compound 83C (0.32 g, yield 100%).
6- (3,5-二甲基 -4-硝基苯基） -6-氮杂螺 [2.5]辛烷 （化合物 83D)  6-(3,5-Dimethyl-4-nitrophenyl)-6-azaspiro[2.5]octane (Compound 83D)
将化合物 83C (0.3g,1.6mmol) ， 5-氟 -1,3-二甲基 -2-硝基苯 （0.26 g， 1.6 mmol) 的乙腈溶 液（10mL)加入封管中， 再加入碳酸铯（ 1.6 g， 4.8 mmol) 。 120°C搅拌 18小时， LCMS 监 测反应结束。 将反应体系倒入圆底烧瓶， 真空旋干， 柱层析 （石油醚： 酸乙酯 =100:1〜60:1) 得到化合物 83D (0.25 g， 收率 60%) 。  Compound 83C (0.3 g, 1.6 mmol), 5-fluoro-1,3-dimethyl-2-nitrobenzene (0.26 g, 1.6 mmol) in acetonitrile (10 mL) was added to a sealed tube, and then cesium carbonate was added. (1.6 g, 4.8 mmol). After stirring at 120 ° C for 18 hours, LCMS monitored the end of the reaction. The reaction system was poured into a round bottom flask, and the mixture was evaporated to dryness. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
2，6-二甲基 -4- (6-氮杂螺 [2.5]辛烷基） 苯胺 （化合物 83E)  2,6-Dimethyl-4-(6-azaspiro[2.5]octyl)aniline (Compound 83E)
将化合物 83D (0.25 g， 0.96 mmol)和连二亚硫酸钠 (1.32 g， 7.7 mmol) 的甲醇 (20 mL) 和水 （2mL) 的混合溶液加入封管中。 90°C反应 1小时， LCMS 监测反应完成。 将反应体系 通过滤纸过滤， 将滤液旋干。 得到的白色固体用乙酸乙酯洗涤过滤除去剩余的盐， 将滤液旋 干得到化合物 83E (0.18 g， 收率 82%)。 N-(2，6-二甲基 -4- (6-氮杂螺 [2.5]辛烷基） 苯基) -3,3-二甲基丁酰胺 （化合物 83 ) 本品由 3，3-二甲基丁酰氯和化合物 83E按照化合物 80的制备方法合成， 收率 12%。A mixed solution of compound 83D (0.25 g, 0.96 mmol) and sodium dithionite (1.32 g, 7.7 mmol) in methanol (20 mL) and water (2 mL) was added to a sealed tube. The reaction was carried out at 90 ° C for 1 hour, and the reaction was monitored by LCMS. The reaction system was filtered through a filter paper, and the filtrate was spun dry. The obtained white solid was washed with ethyl acetate and filtered to remove the residue, and the filtrate was evaporated to afford compound 83E (0.18 g, yield 82%). N-(2,6-Dimethyl-4-(6-azaspiro[2.5]octyl)phenyl)-3,3-dimethylbutyramide (Compound 83) This product consists of 3,3- Dimethylbutyryl chloride and compound 83E were synthesized according to the method for the preparation of compound 80 in a yield of 12%.
NMR (400 MHz, CDC13) δ: 7.76 (s， 1Η), 7.46(s, 2H)， 3.44(brs, 4H)， 2.38 (s， 2H), 2.25 (brs, 7H)NMR (400 MHz, CDC13) δ: 7.76 (s, 1Η), 7.46 (s, 2H), 3.44 (brs, 4H), 2.38 (s, 2H), 2.25 (brs, 7H)
1.25 (brs, 2H), 1.15(s, 10H), 0.53(brs, 4H). 1.25 (brs, 2H), 1.15(s, 10H), 0.53(brs, 4H).
实施例八十四  Example eighty four
N-(2，6-二甲基 l-4-(5-氮 2.4]-5-庚烷基)苯 -3，3-二甲基丁酰胺的制备
Figure imgf000078_0001
Preparation of N-(2,6-dimethyll-4-(5-nitro2.4]-5-heptyl)benzene-3,3-dimethylbutanamide
Figure imgf000078_0001
N-苄氧羰基 -3-甲叉基吡咯 （化合物 84A)  N-benzyloxycarbonyl-3-methylidenepyrrole (Compound 84A)
本品由 N-Cbz-3-吡咯烷酮按照化合物 83A的制备方法合成，收率 58%， MS: 218.1 (M+H+). N-苄氧羰基 -5-氮杂螺 [2.4]庚烷 （化合物 84B) This product is synthesized from N-Cbz-3-pyrrolidone according to the preparation method of compound 83A, yield 58%, MS: 218.1 (M+H + ). N-benzyloxycarbonyl-5-azaspiro[2.4]heptane ( Compound 84B)
本品由化合物 84A按照化合物 83B的制备方法合成， 60%收率。 MS: 232.2 (M+H+). 5-氮杂螺 [2.4]庚烷氢溴酸盐 （化合物 84C) This product was synthesized from Compound 84A according to the preparation method of Compound 83B, 60% yield. MS: 232.2 (M+H + ). 5-Azaspiro[2.4]heptane hydrobromide (Compound 84C)
本品由化合物 84B按照化合物 83C的制备方法合成， 收率 94%。  This product was synthesized from Compound 84B according to the preparation method of Compound 83C, yield 94%.
N-(2，6-二甲基 1-4-(5-氮杂螺 [2.4]-5-庚烷基)苯基) -3,3-二甲基丁酰胺 （化合物 84) 本品由化合物 84C和 N- (4-溴代 -2， 6-二甲基苯基） -3-甲基丁酰胺按照化合物 5的制备 方法合成， 收率 64%。 MS: 315.3 (M+H+). 1H NMR (DMSO, 400 MHz) δ: 8.80 (s, 1H), 6.19 (s， 2H)， 3.34 (t, J= 6.4 Hz, 2H)， 3.12 (s， 2H), 2.15 (s， 2H), 2.06 (s， 6H)， 1.88 (m， 2H), 1.04(s, 9H)， 0.60 (m， 4H).  N-(2,6-Dimethyl1-4-(5-azaspiro[2.4]-5-heptyl)phenyl)-3,3-dimethylbutanamide (Compound 84) Compound 84C and N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide were synthesized according to the method for the preparation of compound 5, yield 64%. MS: 315.3 (M+H+). 1H NMR (DMSO, 400 MHz) δ: 8.80 (s, 1H), 6.19 (s, 2H), 3.34 (t, J = 6.4 Hz, 2H), 3.12 (s, 2H) ), 2.15 (s, 2H), 2.06 (s, 6H), 1.88 (m, 2H), 1.04 (s, 9H), 0.60 (m, 4H).
实施例八十五  Example eighty five
N-(2，6-二甲 -4-(5-氮杂 [2.5]-5-辛烷基)苯基 )-3，3-二甲
Figure imgf000078_0002
N-(2,6-dimethyl-4-(5-aza[2.5]-5-octyl)phenyl)-3,3-dimethyl
Figure imgf000078_0002
N-苄氧羰基 -3-甲叉基哌啶 （化合物 85A)  N-benzyloxycarbonyl-3-methylidenepiperidine (Compound 85A)
本品由 N-Cbz-3-哌啶酮按照化合物 83A的制备方法合成， 收率 74%。 MS: 232 (M+H+). N-苄氧羰基 -5-氮杂螺 [2.5]辛烷 （化合物 85B) This product was synthesized from N-Cbz-3-piperidone according to the preparation method of Compound 83A in a yield of 74%. MS: 232 (M+H + ). N-benzyloxycarbonyl-5-azaspiro[2.5]octane (Compound 85B)
本品由化合物 85 A按照化合物 83B的制备方法合成， 86%收率。 MS: 246 (M+H+). This product was synthesized from the compound 85 A according to the preparation method of the compound 83B, 86% yield. MS: 246 (M+H + ).
5-氮杂螺 [2.5]辛烷溴化氢盐 （化合物 85C)  5-Azaspiro[2.5]octane hydrogen bromide (Compound 85C)
本品由化合物 85B按照化合物 83C的制备方法合成， 收率 100%。 MS: 112 (M+H+). N-(2，6-二甲基 -4-(5-氮杂 [2.5]-5-辛烷基)苯基) -3，3-二甲基丁酰胺 （化合物 85 ) 本品由化合物 85C和 N- (4-溴代 -2， 6-二甲基苯基） -3， 3-二甲基丁酰胺按照化合物 5 的制备方法合成，收率 29%。MS: 329(M+H+). 1H NMR (400 MHz, DMSO) δ: 8.86 (s, 1H)， 6.57(s: 2H)， 3.10(t, J= 4.4 Hz, 2H), 2.83 (s, 2H), 2.15 (s, 2H), 2.06 (s, 6H), 1.65-1.75(m, 2H), 1.36(t, J = 5.6 Hz, 2H), 1.04(s, 9H)， 0.39-0.45(m, 2H), 0.26-0.34(m, 2H). This product was synthesized from the compound 85B according to the preparation method of the compound 83C, yield 100%. MS: 112 (M+H + ). N-(2,6-Dimethyl-4-(5-aza[2.5]-5-octyl)phenyl)-3,3-dimethylbutanamide (Compound 85) This product is compound 85C And N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide was synthesized according to the preparation method of compound 5 in a yield of 29%. MS: 329 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 8.86 (s, 1H), 6.57 (s : 2H), 3.10 (t, J = 4.4 Hz, 2H), 2.83 (s, 2H), 2.15 (s, 2H), 2.06 (s, 6H), 1.65-1.75 (m, 2H), 1.36 (t, J = 5.6 Hz, 2H), 1.04 (s, 9H), 0.39-0.45 (m) , 2H), 0.26-0.34 (m, 2H).
实施例八十六  Example eighty six
Ν-(4-( -二氢螺 [ -1，4'-哌啶 基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺的制备  Preparation of Ν-(4-(-dihydrospiro[-1,4'-piperidinyl]-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000079_0001
Figure imgf000079_0001
叔丁基螺 [茚 -1，4'-哌啶] -Γ-羧酸酯 （化合物 86A)  Tert-butylspiro[茚 -1,4'-piperidine]-indole-carboxylate (Compound 86A)
在 250 ml茄形瓶中加入化合物茚 （3.5 g， 30mmol)和干燥的四氢呋喃 （5 ml) ， 在冰浴 条件下， 双 (三甲硅基)氨基锂 （60 ml， 1M的四氢呋喃溶液）慢慢加入 250ml茄形瓶中。 搅 拌 30分钟后，加入 Ν,Ν-双 (2-氯乙基)氨基甲酸叔丁酯（6.8g，281 mmol)的四氢呋喃溶液 40ml。 在冰浴下搅拌 30分钟后， 恢复到室温搅拌 2h， 然后柱层析得化合物 86A (5 g， 58%收率） 。  Add the compound hydrazine (3.5 g, 30 mmol) and dry tetrahydrofuran (5 ml) to a 250 ml eggplant-shaped flask. Under ice bath, bis(trimethylsilyl)amide lithium (60 ml, 1 M in tetrahydrofuran) slowly Add to a 250ml eggplant bottle. After stirring for 30 minutes, 40 ml of a solution of tert-butyl hydrazine, bis-(2-chloroethyl)carbamate (6.8 g, 281 mmol) in tetrahydrofuran was added. After stirring for 30 minutes in an ice bath, it was stirred at room temperature for 2 h and then was purified by column chromatography to afford compound 86A (5 g, 58% yield).
螺 [茚 -1，4'-哌啶] (化合物 86B)  Snail [茚 -1,4'-piperidine] (Compound 86B)
化合物 86A (4 g, 14 mmol) 加入到三氟乙酸 （10 ml) 和二氯甲烷 （10 ml) 中， 在室温 条件下搅拌 2个小时后， 浓縮得到化合物 86B (2.4 g， 93%收率） 。  Compound 86A (4 g, 14 mmol) was added to EtOAc (EtOAc) (EtOAc) Rate).
2，3-二氢螺 [茚 -1，4'-哌啶] (化合物 86C)  2,3-Dihydrospiro [茚 -1,4'-piperidine] (Compound 86C)
本品由化合物 86B按照化合物 29B的制备方法合成， 98%收率。  This product was synthesized from Compound 86B according to the preparation method of Compound 29B, 98% yield.
Γ-(3，5-二甲基 -4-硝基苯基) -2,3-二氢螺 [茚 -1，4'-哌啶] (化合物 86D)  Γ-(3,5-Dimethyl-4-nitrophenyl)-2,3-dihydrospiro[茚-1,4'-piperidine] (Compound 86D)
本品由化合物 86C和 6-氯 -2,4-二甲基 -3-硝基苯按照化合物 53Α的制备方法合成， 40%收 率。  This product is synthesized from compound 86C and 6-chloro-2,4-dimethyl-3-nitrobenzene according to the preparation method of compound 53Α, 40% yield.
4-(2，3-二氢螺 [茚 -1，4'-哌啶] -Γ-基) -2,6-二甲基苯胺 （化合物 86Ε)  4-(2,3-Dihydrospiro[茚-1,4'-piperidine]-indolyl)-2,6-dimethylaniline (Compound 86Ε)
本品由化合物 86D按照化合物 80C的制备方法， 室温反应 16h， 97%收率。  This product was reacted with compound 86D according to the preparation method of compound 80C at room temperature for 16 h, 97% yield.
N-(4-(2，3-二氢螺 [茚 -1，4'-哌啶] -Γ-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 86) 本品由化合物 86E按照化合物 2的制备方法合成， 38%收率。 1H NMR (400 MHz, DMSO) δ: 8.89 (s， 1H), 7.14-7.24 (m， 4H)， 6.7 (m， 2H)， 3.65 (d, J= 12.8 Hz， 2H), 2.80-2.89 (m， 4H)， 2.18 (m， 2H), 2.10 (m， 6H)， 1.90-2.01 (m， 4H)， 1.58 (m， 2H), 1.26 (m， 1H), 1.06 (s, 9H). N-(4-(2,3-Dihydrospiro[茚-1,4'-piperidine]-indolyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 86) This product was synthesized from Compound 86E according to the preparation method of Compound 2, with a yield of 38%. 1H NMR (400 MHz, DMSO) δ: 8.89 (s, 1H), 7.14-7.24 (m, 4H), 6.7 (m, 2H), 3.65 (d, J = 12.8 Hz, 2H), 2.80-2.89 (m , 4H), 2.18 (m, 2H), 2.10 (m, 6H), 1.90-2.01 (m, 4H), 1.58 (m, 2H), 1.26 (m, 1H), 1.06 (s, 9H).
实施例八十七  Example 87
N-(4-(8-氮螺 [4.5]葵烷 -8 -基甲基-2，6-二甲基苯) -3，3-二甲基丁酰胺 （化合物 87) 的制备
Figure imgf000080_0001
Preparation of N-(4-(8-azaspiro[4.5] hexane-8-ylmethyl-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 87)
Figure imgf000080_0001
本品由 8-氮螺 [4.5]葵烷和 N-(4-甲酰基 -2,6-二甲苯基) -3,3-二甲基丁酰胺按照化合物 74的 制备方法， 回流 2d， 8.1%收率。 MS: 371 [M+H]+.1HNMR ( 4-Methanol 400ΜΗζ) δ: 7.09(s, 1H)， 3.47 (s, 2H), 2.46 (brs, 4H)， 2.34 (s, 2H), 2.24 (s, 6H)， 1.65-1.62 (m， 4H)， 1.54-1.51 (m， 4H)， 1.47-1.43 (m， 4H)， 1.16 (s, 9H)。 This product consists of 8-aziro[4.5]olane and N-(4-formyl-2,6-dimethylphenyl)-3,3-dimethylbutyramide according to the preparation method of compound 74, reflux 2d, 8.1 % yield. MS: 371 [M+H] + .1HNMR (4-Methanol 400 ΜΗζ) δ: 7.09 (s, 1H), 3.47 (s, 2H), 2.46 (brs, 4H), 2.34 (s, 2H), 2.24 (s , 6H), 1.65-1.62 (m, 4H), 1.54-1.51 (m, 4H), 1.47-1.43 (m, 4H), 1.16 (s, 9H).
实施例八十八  Example eighty eight
N-( -二甲基 -4-(4-(2-氟苯基)哌啶 -1-基)苯基) -3，3-二甲基丁酰胺盐酸盐的制备
Figure imgf000080_0002
Preparation of N-(-dimethyl-4-(4-(2-fluorophenyl)piperidin-1-yl)phenyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000080_0002
叔丁基 4-(2-氟苯基 )-5，6-二氢吡啶 -1(2H)-甲酸酯 （化合物 88A)  tert-Butyl 4-(2-fluorophenyl)-5,6-dihydropyridine-1(2H)-formate (Compound 88A)
本品由 2-氟苯基硼酸和叔丁基 4- (三氟甲磺酸酯) -5,6-二氢吡啶 -1(2H)-甲酸酯按照化合物 19A的制备方法合成， 94% 收率。  This product is synthesized from 2-fluorophenylboronic acid and tert-butyl 4-(trifluoromethanesulfonate)-5,6-dihydropyridine-1(2H)-formate according to the preparation method of compound 19A, 94% Yield.
叔丁基 4-(2-氟苯基) -哌啶 -1-甲酸酯 （化合物 88B)  tert-Butyl 4-(2-fluorophenyl)-piperidine-1-carboxylate (Compound 88B)
本品由化合物 88A按照化合物 29B的制备方法， 室温反应 3h， 99%产率。  This product was reacted with compound 88A according to the preparation method of compound 29B at room temperature for 3 h, 99% yield.
4-(2-氟苯基)哌啶 （化合物 88C)  4-(2-fluorophenyl)piperidine (Compound 88C)
本品由化合物 88B按照化合物 29的制备方法合成。  This product was synthesized from Compound 88B according to the preparation method of Compound 29.
1-(3，5-二甲基 -4-硝基苯基) -4-(2-氟苯基)哌啶 （化合物 88D)  1-(3,5-Dimethyl-4-nitrophenyl)-4-(2-fluorophenyl)piperidine (Compound 88D)
本品由化合物 88C和 4-氟 -2,6-二甲基硝基苯按照化合物 53A的制备方法合成， 46%收率。 2，6-二甲基 -4-(4-(2-氟苯基)哌啶 -1-基)胺 （化合物 88E)  This product was synthesized from Compound 88C and 4-fluoro-2,6-dimethylnitrobenzene according to the preparation of Compound 53A, 46% yield. 2,6-Dimethyl-4-(4-(2-fluorophenyl)piperidin-1-yl)amine (Compound 88E)
本品由化合物 88D按照化合物 81C的制备方法， 室温反应 12h， 99%收率。  This product was reacted with compound 88D according to the preparation method of compound 81C at room temperature for 12 h, 99% yield.
N-(2，6-二甲基 -4-(4-(2-氟苯基)哌啶 -1-基)苯基) -3,3-二甲基丁酰胺盐酸盐 （化合物 88) 本品由 3，3-二甲基丁酰氯和化合物 88E按照化合物 80的制备方法合成，产品用盐酸*** 溶液酸化得盐酸盐， 79%收率。 MS: 397.3 (M+H+).1H NMR (400 MHz, CDC13) δ: 7.26-7.00 (m， 4H)6.70 (s, 2H), 6.53 (s, 1H), 3.76 (d, J= 12.0 Hz, 2H), 3.05-2.97 (m， 1H), 2.85-2.79 (m， 2H), 2.27 (s， 2H), 2.21 (s， 6H)， 1.93-1.87 (m， 4H)， 1.15 (s， 9H). N-(2,6-Dimethyl-4-(4-(2-fluorophenyl)piperidin-1-yl)phenyl)-3,3-dimethylbutanamide hydrochloride (Compound 88) This product was synthesized from 3,3-dimethylbutyryl chloride and compound 88E according to the preparation method of compound 80. The product was acidified with hydrochloric acid ethyl ether to give the hydrochloride salt, 79% yield. MS: 397.3 (M+H + ).1H NMR (400 MHz, CDC1 3 ) δ: 7.26-7.00 (m, 4H) 6.70 (s, 2H), 6.53 (s, 1H), 3.76 (d, J = 12.0 Hz, 2H), 3.05-2.97 (m, 1H), 2.85-2.79 (m, 2H), 2.27 (s, 2H), 2.21 (s, 6H), 1.93-1.87 (m, 4H), 1.15 (s, 9H).
实施例八十九  Example eighty nine
N-(2，6-二甲基 -4-(4-(2- (三氟甲基)苯基)哌啶 -1-基)苯基) -3，3-二甲基丁酰胺的制备  Preparation of N-(2,6-dimethyl-4-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)phenyl)-3,3-dimethylbutanamide
Figure imgf000081_0001
Figure imgf000081_0001
叔丁基 4-(2- (三氟甲基)苯基) -5，6-二氢吡啶 -1(2H)-甲酸酯 （化合物 89A)  tert-Butyl 4-(2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-formate (Compound 89A)
本品由 2-三氟甲基苯基硼酸和叔丁基 4- (三氟甲磺酸酯) -5,6-二氢吡啶 -1(2H)-甲酸酯按照 化合物 19A的制备方法合成， 76% 收率。  This product is synthesized from 2-trifluoromethylphenylboronic acid and tert-butyl 4-(trifluoromethanesulfonate)-5,6-dihydropyridine-1(2H)-formate according to the preparation method of compound 19A. , 76% yield.
叔丁基 4-(2- (三氟甲基)苯基) -哌啶 -1-甲酸酯 （化合物 89B)  tert-Butyl 4-(2-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (Compound 89B)
本品由化合物 89A按照化合物 29B的制备方法合成， 99%收率。  This product was synthesized from Compound 89A according to the preparation method of Compound 29B, yield 99%.
4-(2- (三氟甲基)苯基哌啶 （化合物 89C)  4-(2-(Trifluoromethyl)phenyl piperidine (Compound 89C)
本品由化合物 89B按照化合物 29的制备方法合成。  This product was synthesized from Compound 89B according to the method for producing Compound 29.
1-(3，5-二甲基 -4-硝基苯基) -4-(2- (三氟甲基)苯基)哌啶 （化合物 89D)  1-(3,5-Dimethyl-4-nitrophenyl)-4-(2-(trifluoromethyl)phenyl)piperidine (Compound 89D)
本品由化合物 89C和 4-氟 -2,3-二甲基硝基苯按照 53A的制备方法合成， 4%收率。  This product was synthesized from Compound 89C and 4-fluoro-2,3-dimethylnitrobenzene according to the preparation method of 53A, 4% yield.
2，6-二甲基 -4-(4-(2- (三氟甲基)苯基)哌啶 -1-基)胺 （化合物 89E)  2,6-Dimethyl-4-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)amine (Compound 89E)
本品由化合物 89D按照化合物 80C的制备方法合成。  This product was synthesized from Compound 89D according to the preparation method of Compound 80C.
N-(2，6-二甲基 -4-(4-(2- (三氟甲基)苯基)哌啶 -1-基)苯基) -3,3-二甲基丁酰胺 （化合物 89) 本品由化合物 89E和 3， 3-二甲基丁酰氯按照化合物 80的制备方法合成， 58%收率。 MS: 447.3 (M+H+).1H NMR (400 MHz, CDC13) δ: 7.65 (d, J= 8.0 Hz 1H) 7.53 (d, J= 8.0 Hz, 2H), 7.32 (d, J= 8.0 Hz, 1H), 6.74 (s, 2H), 6.56 (s, 1H), 3.78 (d, J= 12.0 Hz, 2H), 3.08 (m, 1H), 2.90 (m: 2H), 2.30 (s， 2H), 2.24(s, 6H)， 1.90 (m， 4.0H), 1.17 (s, 9H). N-(2,6-Dimethyl-4-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)phenyl)-3,3-dimethylbutanamide (compound) 89) This product was synthesized from Compound 89E and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 80, 58% yield. MS: 447.3 (M+H+).1H NMR (400 MHz, CDC1 3 ) δ: 7.65 (d, J = 8.0 Hz 1H) 7.53 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz , 1H), 6.74 (s, 2H), 6.56 (s, 1H), 3.78 (d, J = 12.0 Hz, 2H), 3.08 (m, 1H), 2.90 (m : 2H), 2.30 (s, 2H) , 2.24(s, 6H), 1.90 (m, 4.0H), 1.17 (s, 9H).
实施例九十  Example ninety
N- (4- (4- (3-氟苯基） 哌啶 -1-基） -2， 6-二甲基苯基） 3， 3-二甲基丁酰胺盐酸盐的制
Figure imgf000082_0001
Preparation of N-(4-(4-(3-fluorophenyl)piperidin-1-yl)-2,6-dimethylphenyl) 3,3-dimethylbutanamide hydrochloride
Figure imgf000082_0001
叔丁基 -4- (3-氟苯基） -5， 6-二氢吡啶 -1 (2H) -羧酸酯 （化合物 90A)  tert-Butyl-4-(3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Compound 90A)
本品由 3-氟苯基硼酸和叔丁基 -4-三氟甲磺酰基 -5， 6-二氢吡啶 -1 (2H) -羧酸酯按照化合 物 19A的制备方法合成， 77%收率。  This product is synthesized from 3-fluorophenylboronic acid and tert-butyl-4-trifluoromethanesulfonyl-5,6-dihydropyridine-1 (2H)-carboxylate according to the preparation method of compound 19A, 77% yield .
叔丁基 -4- (3-氟苯基） 哌啶 -1羧酸酯 （化合物 90B)  tert-Butyl-4-(3-fluorophenyl)piperidine-1carboxylate (Compound 90B)
本品由化合物 90A按照化合物 29B的制备方法合成， 95%收率。 MS: 224.1 (M-56+H+). 4- (3-氟苯基） 哌啶 （化合物 90C) This product was synthesized from Compound 90A according to the preparation method of Compound 29B, 95% yield. MS: 224.1 (M-56+H + ). 4- (3-fluorophenyl)piperidine (Compound 90C)
本品由化合物 90B按照化合物 29的制备方法合成， 100%收率。  This product was synthesized from Compound 90B according to the preparation method of Compound 29, 100% yield.
1- ( 3， 5-二甲基 -4-硝基苯基） 4- ( 3-氟苯基） 哌啶 （化合物 90D)  1-(3,5-Dimethyl-4-nitrophenyl) 4-(3-fluorophenyl)piperidine (Compound 90D)
本品由化合物 90C和 4-氟 -2,3-二甲基硝基苯按照 53A的制备方法合成， 70%收率。 MS: 329.2 (M+H+)。 This product is synthesized from the compound 90C and 4-fluoro-2,3-dimethylnitrobenzene according to the preparation method of 53A, 70% yield. MS: 329.2 (M+H + ).
4- (4- (3-氟苯基） 哌啶小基） -2， 6-二甲基胺 （化合物 90E)  4-(4-(3-Fluorophenyl) piperidinyl) -2,6-dimethylamine (Compound 90E)
本品由化合物 90D按照化合物 83E的制备方法合成， 98%收率。 MS: 299.2 (M+H+). N- (4- (4- (3-氟苯基） 哌啶 -1-基） -2， 6-二甲基苯基） 3， 3-二甲基丁酰胺盐酸盐 （化 合物 90) This product was synthesized from Compound 90D according to the preparation method of Compound 83E, 98% yield. MS: 299.2 (M+H + ). N-(4-(4-(3-fluorophenyl)piperidin-1-yl)-2,6-dimethylphenyl) 3, 3-dimethyl Butyramide hydrochloride (compound 90)
本品由化合物 90E按照化合物 80的制备方法，室温搅拌 lh， 产品用盐酸***酸化得盐 酸盐， 99% 收率。 MS: 397.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.37 (brs, 1Η), 7.59 (brs, 1H), 7.40-7.45 (dd， Ji = J2 = 7.6 Hz, 2H), 7.08-7.18 (m， 3H), 3.62-3.69 (brs, 3.5H), 2.51 (brs, 2H), 2.25 (s， 2H), 2.21 (s， 6H)， 2.04-2.07 (brs, 2.5H), 1.07 (s， 9H). This product is prepared from the compound 90E according to the method of the compound 80, stirring at room temperature for 1 hour, and the product is acidified with hydrochloric acid diethyl ether to give the hydrochloride salt, 99% yield. MS: 397.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.37 (brs, 1 Η), 7.59 (brs, 1H), 7.40-7.45 (dd, Ji = J 2 = 7.6 Hz, 2H ), 7.08-7.18 (m, 3H), 3.62-3.69 (brs, 3.5H), 2.51 (brs, 2H), 2.25 (s, 2H), 2.21 (s, 6H), 2.04-2.07 (brs, 2.5H) ), 1.07 (s, 9H).
实施例九 ^一  Embodiment IX ^1
N- (4- (4- (3-氯苯基） 哌啶 -1-基） -2， 6-二甲基苯基） 3， 3-二甲基丁酰胺盐酸盐的制
Figure imgf000083_0001
Preparation of N-(4-(4-(3-chlorophenyl)piperidin-1-yl)-2,6-dimethylphenyl) 3,3-dimethylbutanamide hydrochloride
Figure imgf000083_0001
叔丁基 -4- (3-氯苯基） -5， 6-二氢吡啶 -1 (2H) -羧酸酯 （化合物 91A)  tert-Butyl-4-(3-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Compound 91A)
本品由 3-氯苯基硼酸和叔丁基 -4-三氟甲磺酰基 -5， 6-二氢吡啶 -1 (2H) -羧酸酯按照化合 物 19A制备方法合成， 95%收率。 MS: 238.1 (M-56+H+). This product was synthesized from 3-chlorophenylboronic acid and tert-butyl-4-trifluoromethanesulfonyl-5,6-dihydropyridine-1 (2H)-carboxylate according to the preparation method of compound 19A, 95% yield. MS: 238.1 (M-56+H + ).
叔丁基 -4- (3-氯苯基） 哌啶 -1羧酸酯 （化合物 91B)  tert-Butyl-4-(3-chlorophenyl)piperidine-1carboxylate (Compound 91B)
本品由化合物 91A按照化合物 29B的制备方法合成， 94%收率。 MS: 240.1 (M-56+H+). 4- (3-氯苯基） 哌啶 （化合物 91C) This product was synthesized from Compound 91A according to the preparation method of Compound 29B, yield 94%. MS: 240.1 (M-56+H + ). 4- (3-chlorophenyl)piperidine (Compound 91 C)
本品由化合物 91C按照化合物 29的制备方法合成， 100%收率。 MS: 196.1 (M+H+). 1- ( 3， 5-二甲基 -4-硝基苯基） 4- ( 3-氯苯基） 哌啶 （化合物 91D) This product was synthesized from Compound 91C according to the preparation method of Compound 29, 100% yield. MS: 196.1 (M+H + ). 1-(3,5-Dimethyl-4-nitrophenyl) 4-(3-chlorophenyl)piperidine (Compound 91D)
本品由化合物 91C和 4-氟 -2,6-硝基苯按照化合物 53A的制备方法合成， 31%收率。 4- (4- (3-氯苯基） 哌啶小基） -2， 6-二甲基胺 （化合物 91E)  This product was synthesized from Compound 91C and 4-fluoro-2,6-nitrobenzene according to the preparation method of Compound 53A, 31% yield. 4-(4-(3-Chlorophenyl) piperidinyl) -2,6-dimethylamine (Compound 91E)
本品由化合物 91D按照化合物 83E的制备方法合成， 97%收率。 MS: 315.2 (； M+H+)。 N- (4- (4- (3-氯苯基） 哌啶 -1-基） -2， 6-二甲基苯基） 3， 3-二甲基丁酰胺盐酸盐 （化 合物 91 ) This product was synthesized from Compound 91D according to the preparation method of Compound 83E, 97% yield. MS: 315.2 (; M+H + ). N-(4-(4-(3-Chlorophenyl)piperidin-1-yl)-2,6-dimethylphenyl) 3,3-dimethylbutanamide hydrochloride (Compound 91)
本品由化合物 91E和 3，3-二甲基丁酰氯按照化合物 80的制备方法合成， 29% 收率。 MS: 413.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.33 (brs, 1Η), 7.29-7.58 (m， 6H)， 3.63-3.65 (m, 3.5H), 2.98 (brs, 1H)， 2.31-2.42 (brs, 2H), 2.25 (s, 2H), 2.21 (s, 6H)， 1.07-2.06 (m， 2.5H), 1.07 (s, 9H).  This product was synthesized from Compound 91E and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 80, 29% yield. MS: 413.2 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.33 (brs, 1 Η), 7.29-7.58 (m, 6H), 3.63-3.65 (m, 3.5H), 2.98 (brs) , 1H), 2.31-2.42 (brs, 2H), 2.25 (s, 2H), 2.21 (s, 6H), 1.07-2.06 (m, 2.5H), 1.07 (s, 9H).
实施例九十二  Example ninety two
N- (4- (4- (3-三氟甲基苯基） 哌啶 -1-基） -2， 6-二甲基苯基） 3， 3-二甲基丁酰胺盐酸 盐的制备
Figure imgf000084_0001
Preparation of N-(4-(4-(3-trifluoromethylphenyl)piperidin-1-yl)-2,6-dimethylphenyl) 3,3-dimethylbutanamide hydrochloride
Figure imgf000084_0001
叔丁基 -4- (3-三氟甲基苯基) -5， 6-二氢吡啶 -1 (2H) -羧酸酯 (化合物 92A)  tert-Butyl-4-(3-trifluoromethylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Compound 92A)
本品由 3-三氟甲基苯基硼酸和叔丁基 -4-三氟甲磺酰基 -5， 6-二氢吡啶 -1 (2H) -羧酸酯按 照化合物 19A制备方法合成， 100%收率。 MS: 272.1 (M-56+H+). This product is synthesized from 3-trifluoromethylphenylboronic acid and tert-butyl-4-trifluoromethanesulfonyl-5,6-dihydropyridine-1 (2H)-carboxylate according to the preparation method of compound 19A, 100% Yield. MS: 272.1 (M-56+H + ).
叔丁基 -4- (3-三氟甲基苯基） 哌啶 -1羧酸酯 （化合物 92B)  tert-Butyl-4-(3-trifluoromethylphenyl)piperidine-1carboxylate (Compound 92B)
本品由化合物 92A按照化合物 29B的制备方法合成， 86%收率。 MS: 274.1 (M-56+H+). 4- (3-三氟甲基苯基） 哌啶 （化合物 92C) This product was synthesized from Compound 92A according to the preparation method of Compound 29B, 86% yield. MS: 274.1 (M-56+H + ). 4- (3-trifluoromethylphenyl)piperidine (Compound 92C)
本品由化合物 92B按照化合物 29的制备方法合成， 100%收率。 MS: 230.1 (M+H+).This product was synthesized from Compound 92B according to the preparation method of Compound 29, 100% yield. MS: 230.1 (M+H + ).
1- ( 3， 5-二甲基 -4-硝基苯基） 4- ( 3-三氟甲基苯基） 哌啶 （化合物 92D ) 本品由化合物 92C和 4-氟 -2,6-二甲基硝基苯按照化合物 53A的制备方法合成， 23%收率。1-(3,5-Dimethyl-4-nitrophenyl) 4-(3-trifluoromethylphenyl)piperidine (Compound 92D) This product consists of compound 92C and 4-fluoro-2,6- Dimethylnitrobenzene was synthesized according to the preparation method of Compound 53A in 23% yield.
MS: 379.2 (M+H+). MS: 379.2 (M+H+).
4- (4- (3-三氟甲基苯基） 哌啶小基） -2， 6-二甲基胺 （化合物 92E)  4-(4-(3-Trifluoromethylphenyl) piperidinyl) -2,6-dimethylamine (Compound 92E)
本品由化合物 92D按照化合物 83E的制备方法合成， 95%收率。 MS: 349.2 (M+H+).This product was synthesized from the compound 92D according to the preparation method of the compound 83E, 95% yield. MS: 349.2 (M+H + ).
N- (4- (4- (3-三氟甲基苯基） 哌啶 -1-基） -2， 6-二甲基苯基） 3， 3-二甲基丁酰胺盐酸 盐 （化合物 92) N-(4-(4-(3-trifluoromethylphenyl)piperidin-1-yl)-2,6-dimethylphenyl) 3,3-dimethylbutanamide hydrochloride (compound) 92)
本品由化合物 92E和 3，3-二甲基丁酰氯按照化合物 80的制备方法合成， 68% 收率。 MS: 447.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.90 (s, 1H), 7.56-7.64 (m, 4H), 6.69 (s, 2H), 3.79 (d, J= 12.4 Hz, 2H), 2.70-2.81 (m， 3H), 2.18 (s, 2H), 2.10 (s, 6H)， 1.77-1.90 (m， 4H)， 1.06 (s, 9H). This product was synthesized from Compound 92E and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 80 in 68% yield. MS: 447.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.90 (s, 1H), 7.56-7.64 (m, 4H), 6.69 (s, 2H), 3.79 (d, J = 12.4 Hz, 2H), 2.70-2.81 (m, 3H), 2.18 (s, 2H), 2.10 (s, 6H), 1.77-1.90 (m, 4H), 1.06 (s, 9H).
实施例九十三  Example ninety three
N-(4-(4-(4-氟苯)哌啶 -1-基) -2，6-二甲苯 )-3，3-二甲丁酰胺盐酸盐的制备 Preparation of N-(4-(4-(4-fluorophenyl)piperidin-1-yl)-2,6-xylene)-3,3-dimethylbutanamide hydrochloride
Figure imgf000085_0001
Figure imgf000085_0001
叔丁基 4-(4-氟苯) -5， 6-二氢吡啶 -1(2H)-甲酯 （化合物 93A)  tert-Butyl 4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-methyl ester (Compound 93A)
本品由 4-氟苯硼酸和叔丁基 4-(((三氟甲基)磺酰)氧) -5， 6-二氢吡啶 -1(2H)-甲酯按照化合 物 19A的制备方法合成， 94%收率。  This product is synthesized from 4-fluorobenzeneboronic acid and tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-methyl ester according to the preparation method of compound 19A. , 94% yield.
叔丁基 4- (4-氟苯） 哌啶 -1-甲酯 （化合物 93B)  tert-Butyl 4-(4-fluorophenyl)piperidine-1-methyl ester (Compound 93B)
本品由化合物 93 A按照化合物 29B的制备方法合成， 99%收率。  This product was synthesized from Compound 93 A according to the preparation method of Compound 29B, yield 99%.
4- (4-氟苯） 哌啶 （化合物 93C)  4-(4-fluorophenyl) piperidine (compound 93C)
本品由化合物 93C按照化合物 29的制备方法合成， 93%产率。  This product was synthesized from the compound 93C according to the method for the preparation of compound 29, yield 93%.
1- (3， 5-二甲苯 -4-硝基苯） -4- (4-氟苯） 哌啶 （化合物 93D)  1-(3, 5-dimethylbenzene-4-nitrobenzene)-4-(4-fluorophenyl) piperidine (compound 93D)
本品由化合物 93C和 4-氟 -2,6-二甲基硝基苯按照化合物 53A的制备方法合成， 46% 产 率。  This product was synthesized from compound 93C and 4-fluoro-2,6-dimethylnitrobenzene according to the preparation method of compound 53A, 46% yield.
4- (4- (4-氟苯) 哌啶小基） -2, 6-二甲胺 (化合物 93E)  4-(4-(4-Fluorophenyl) piperidinyl) -2,6-dimethylamine (Compound 93E)
本品由化合物 93D按照化合物 80C的制备方法合成， 85%收率。  This product was synthesized from Compound 93D according to the preparation method of Compound 80C, 85% yield.
N-(4-(4-(4-氟苯)哌啶 -1-基) -2,6-二甲苯 )-3，3-二甲丁酰胺盐酸盐 （化合物 94)  N-(4-(4-(4-fluorophenyl)piperidin-1-yl)-2,6-xylene)-3,3-dimethylbutyramide hydrochloride (Compound 94)
本品由化合物 93E和 3，3-二甲基丁酰氯按照化合物 80的制备方法合成， 64%收率。 MS: 397.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.37 (brs, 1H), 7.63 (brs, 2H), 7.35 (m， 2H), 7.20 (m， 2H), 3.63 (m， 2H), 2.99 (m， 1H), 2.48 (brs, 2H), 2.25 (s， 2H), 2.23 (s， 6H)， 2.01 (m， 2H), 1.09 (s, 9H). This product was synthesized from Compound 93E and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 80, 64% yield. MS: 397.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.37 (brs, 1H), 7.63 (brs, 2H), 7.35 (m, 2H), 7.20 (m, 2H), 3.63 (m, 2H), 2.99 (m, 1H), 2.48 (brs, 2H), 2.25 (s, 2H), 2.23 (s, 6H), 2.01 (m, 2H), 1.09 (s, 9H).
实施例九十四  Example ninety four
N-(4-(4-(4-氯苯)哌啶 -1-基) -2，6-二甲苯 )-3，3-二甲丁酰胺盐酸盐的制备 Preparation of N-(4-(4-(4-chlorophenyl)piperidin-1-yl)-2,6-xylene)-3,3-dimethylbutyramide hydrochloride
Figure imgf000086_0001
Figure imgf000086_0001
叔丁基 4- (4-氯苯) -5， 6-二氢吡啶 -1 (2H) -甲酯 (化合物 94A)  tert-Butyl 4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-methyl ester (Compound 94A)
本品由叔丁基 4-( ((三氟甲基)磺酰基)氧) -5,6-二氢吡啶 -1(2H)-碳酸酯和 4-氯苯硼酸按照 化合物 19A的制备方法合成， 94%收率。  This product is synthesized from tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carbonate and 4-chlorophenylboronic acid according to the preparation method of compound 19A. , 94% yield.
叔丁基 4- (4-氯苯） 哌啶 -1-甲酯 （化合物 94B )  tert-Butyl 4-(4-chlorophenyl)piperidine-1-methyl ester (Compound 94B)
本品由化合物 94A按照化合物 29B的制备方法合成， 99%收率。  This product was synthesized from Compound 94A according to the preparation method of Compound 29B, yield 99%.
4- (4-氯苯） 哌啶 （化合物 94C )  4-(4-chlorophenyl) piperidine (compound 94C)
本品由化合物 94B按照化合物 29的制备方法合成， 90%产率。  This product was synthesized from Compound 94B according to the method for the preparation of Compound 29, 90% yield.
1- ( 3， 5-二甲苯 -4-硝基苯） -4- (4-氯苯） 哌啶 （化合物 94D)  1-( 3, 5-dimethylbenzene-4-nitrobenzene)-4-(4-chlorophenyl) piperidine (compound 94D)
本品由化合物 94C按照化合物 53A的制备方法合成， 30%产率。  This product was synthesized from Compound 94C according to the method for the preparation of Compound 53A, 30% yield.
4- (4- (4-氯苯) 哌啶小基） -2, 6-二甲胺 （化合物 94E)  4-(4-(4-Chlorophenyl) piperidinyl) -2,6-dimethylamine (Compound 94E)
本品由化合物 94D按照化合物 1C的制备方法合成， 84%收率。  This product was synthesized from Compound 94D according to the method for the preparation of Compound 1C, 84% yield.
N- (4- (4- (4-氯苯） 哌啶 -1-基） -2， 6-二甲苯） -3， 3-二甲丁酰胺盐酸盐 （化合物 94) 本品由化合物 94E和 3，3-二甲基丁酰氯按照化合物 80的制备方法， 室温搅拌 2h， 38%收 率。 MS: 413.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.29 (brs, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.35 (d, J= 8.4 Hz, 4H)， 3.63 (m， 4H)， 2.98 (m， 1H), 2.25 (s, 2H), 2.24 (m， 2H), 2.23 (s, 6H)， 1.97 (m， 2H), 1.09 (s, 9H).  N-(4-(4-(4-chlorophenyl)piperidin-1-yl)-2,6-xylene)-3,3-dimethylbutyramide hydrochloride (Compound 94) This product is compound 94E And 3,3-dimethylbutyryl chloride were stirred according to the preparation method of compound 80 at room temperature for 2 h, 38% yield. MS: 413.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.29 (brs, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 4H ), 3.63 (m, 4H), 2.98 (m, 1H), 2.25 (s, 2H), 2.24 (m, 2H), 2.23 (s, 6H), 1.97 (m, 2H), 1.09 (s, 9H) .
实施例九十五  Example ninety five
N-(2，6-二甲基 -4-(l-(4- (三氟甲基)苯基)哌啶 -4-基)苯基) -3，3-二甲基丁酰胺盐酸盐的制备  N-(2,6-Dimethyl-4-(l-(4-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-3,3-dimethylbutyramide hydrochloride Preparation of salt
Figure imgf000086_0002
Figure imgf000086_0002
叔丁基 4-(4- (三氟甲基)苯基) -5,6-二氢吡啶 -1(2H)-碳酸酯 （化合物 95A) 本品由叔丁基 4- (《三氟甲基)磺酰基)氧) -5,6-二氢吡啶 -1(2H)-碳酸酯和 4-三氟甲基苯硼 酸按照化合物 19A的制备方法合成， 73%收率。 tert-Butyl 4-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carbonate (Compound 95A) Preparation of tert-butyl 4-("trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carbonate and 4-trifluoromethylbenzeneboronic acid according to compound 19A Method synthesis, 73% yield.
叔丁基 4- (4- (三氟甲基） 苯基） 哌啶 - 1-碳酸酯 （化合物 95B )  tert-Butyl 4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (Compound 95B)
本品由化合物 95 A按照化合物 29B的制备方法合成， 87%收率。  This product was synthesized from Compound 95 A according to the preparation method of Compound 29B, yield 87%.
4-(4- (三氟甲基)苯基)哌啶 （化合物 95C)  4-(4-(Trifluoromethyl)phenyl)piperidine (Compound 95C)
在冰浴下， 向化合物 95B ( 355 mg， 1.1 mmol) 的四氢呋喃 （10 ml)溶液加入盐酸*** 溶液， 然后在 50 °C搅拌 4小时， 浓縮， 得到化合物 95C粗品 405 mg。  To a solution of the compound 95B (355 mg, 1.1 mmol) in THF (10 ml), EtOAc.
N-(2，6-二甲基 -4-(1-(4- (三氟甲基)苯基)哌啶 -4-基)苯基) -3,3-二甲基丁酰胺盐酸盐 （化合物 N-(2,6-Dimethyl-4-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)phenyl)-3,3-dimethylbutyramide hydrochloride Salt
95 ) 95)
本品由 N-(4-溴 -2,6-二甲苯基) -3,3-二甲基叔丁酰胺和化合物 95C按照化合物 7的制备方 法合成， 15%收率。 MS: 447 [M+H]+. 1H NMR (400 MHz, DMSO) δ: 9.28 (s， 1H), 7.73(d, J= 8.0 Hz, 2H)， 7.54 (d, J= 8.0 Hz, 2H)， 3.65-3.70 (m， 4H)， 3.10(m, 1H)， 2.34 (m， 2H), 2.23 (s， 2H), 2.19 (s， 6H)， 2.10-2.14 (m， 2H), 1.06 (s， 9H). This product was synthesized from N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-tert-butylamide and compound 95C according to the preparation method of compound 7, 15% yield. MS: 447 [M+H] + . 1H NMR (400 MHz, DMSO) δ: 9.28 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H) , 3.65-3.70 (m, 4H), 3.10(m, 1H), 2.34 (m, 2H), 2.23 (s, 2H), 2.19 (s, 6H), 2.10-2.14 (m, 2H), 1.06 (s , 9H).
实施例九十六  Example ninety six
N- (2， 6-二甲基 -4- (4- (吡啶 -3-基) 哌啶小基) 苯基） -3， 3-二甲基丁酰胺盐酸盐的制 备  Preparation of N-(2,6-dimethyl-4-(4-(pyridin-3-yl)piperidinyl)phenyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000087_0001
Figure imgf000087_0001
叔丁基 5'， 6'-二氢 -[3， 4'-二吡啶 ]-Γ (2Ή) -甲酯 （化合物 96A)  tert-Butyl 5',6'-dihydro-[3,4'-dipyridine]-indole (2Ή)-methyl ester (Compound 96A)
本品由吡啶 -3-硼酸和叔丁基 4- ( ( (三氟甲基） 磺酰） 氧） -5， 6-二氢吡啶 -1 (2H) -羧 酸按照化合物 19A的制备方法合成， 79%收率。  This product is synthesized from pyridin-3-boronic acid and tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid according to the preparation method of compound 19A. , 79% yield.
叔丁基 4- (吡啶 -3-基） 哌啶 -1-甲酯 （化合物 96B)  tert-Butyl 4-(pyridin-3-yl)piperidine-1-methyl ester (Compound 96B)
本品由化合物 96A按照化合物 29B的制备方法合成， 94%收率。  This product was synthesized from Compound 96A according to the method for the preparation of Compound 29B, yield 94%.
3- (哌啶 -4-基） 哌啶 （化合物 96C)  3-(piperidin-4-yl)piperidine (Compound 96C)
本品由化合物 96B按照化合物 29的制备方法合成， 93%产率。  This product was synthesized from Compound 96B according to the method for the preparation of compound 29, yield 93%.
N- (2， 6-二甲基 -4- (4- ( B比啶 -3-基） 哌啶小基） 苯基） -3， 3-二甲基丁酰胺盐酸盐 （化 合物 96)  N-(2,6-Dimethyl-4-(4-(B-pyridin-3-yl)piperidinyl)phenyl)-3,3-dimethylbutyramide hydrochloride (Compound 96)
本品由 N- (4-溴 -2， 6-二甲基苯） -3， 3-二甲基丁酰胺和化合物 96C按照化合物 7的制备 方法合成， 51%收率。 MS: 380.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.46 (s, 1Η)， 8.92 (s, 1H), 8.88 (d, J= 6.4 Hz, 1H)， 8.58 (d， J= 6.4 Hz, 1H), 8.13 (m, 1H), 3.65 (m, 4H), 3.28 (m, 1H): 2.26 (s， 2H), 2.25 (m， 2H), 2.22 (s， 6H)， 1.07 (s， 9H). This product was synthesized from N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide and compound 96C according to the preparation method of compound 7, 51% yield. MS: 380.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.46 (s, 1 Η), 8.92 (s, 1H), 8.88 (d, J = 6.4 Hz, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.13 (m, 1H), 3.65 (m, 4H), 3.28 (m, 1H) : 2.26 ( s, 2H), 2.25 (m, 2H), 2.22 (s, 6H), 1.07 (s, 9H).
实施例九十七  Example ninety seven
N-(2，6-二甲基 -4-(l- (吡啶 -4-基)哌啶 -4-基)苯基) -3，3-二甲基丁酰胺盐酸盐的制备  Preparation of N-(2,6-dimethyl-4-(l-(pyridin-4-yl)piperidin-4-yl)phenyl)-3,3-dimethylbutanamide hydrochloride
Figure imgf000088_0001
Figure imgf000088_0001
叔丁基 5，6-二氢 -[4，4'-二吡啶 ]-1(2Η)-碳酸酯 （化合物 97A)  tert-Butyl 5,6-dihydro-[4,4'-dipyridyl]-1(2Η)-carbonate (Compound 97A)
本品由叔丁基 4- (《三氟甲基)磺酰基)氧) -5,6-二氢吡啶 -1(2H)-碳酸酯和吡啶 -4-硼酸按照 化合物 19A的制备方法合成， 92%收率。  This product is synthesized from tert-butyl 4-("trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carbonate and pyridine-4-boronic acid according to the preparation method of compound 19A. 92% yield.
叔丁基 4- (吡啶 -4-基)哌啶 - 1-碳酸酯 （化合物 97B)  tert-Butyl 4-(pyridin-4-yl)piperidine-1-carboxylate (Compound 97B)
本品由化合物 97A按照化合物 29B的制备方法合成， 87%收率。  This product was synthesized from Compound 97A according to the preparation method of Compound 29B, with a yield of 87%.
4- (哌啶 -4-基)吡啶盐酸盐 （化合物 97C)  4-(piperidin-4-yl)pyridine hydrochloride (Compound 97C)
本品由化合物 97B按照化合物 95C的制备方法合成， 得粗品直接投下步反应。  This product is synthesized from the compound 97B according to the preparation method of the compound 95C, and the crude product is directly subjected to a step reaction.
N-(2，6-二甲基 -4-(1- (吡啶 -4-基)哌啶 -4-基)苯基) -3,3-二甲基丁酰胺盐酸盐 （化合物 97) 本品由 N-(4-溴 -2,6-二甲苯基) -3,3-二甲基叔丁酰胺和化合物 97C按照化合物 7的制备方 法合成， 18%收率。 MS: 380 [M+l]+. 1H NMR (400 MHz, DMSO) δ: 9.26 (s, 1H), 8.90(d，J= 6.4 Hz, 2H)， 8.01 (d, J= 6.4 Hz, 2H)， 7.36 (m， 1H), 3.73 (d， 12.4 Hz, 2H), 3.45(m, 2H), 3.25(m, 1H)， 2.34 (m， 2H), 2.23 (s， 2H), 2.18 (s， 6H)， 2.10-2.14 (m， 2H), 1.06 (s， 9H).  N-(2,6-Dimethyl-4-(1-(pyridin-4-yl)piperidin-4-yl)phenyl)-3,3-dimethylbutanamide hydrochloride (Compound 97) This product was synthesized from N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-tert-butylamide and compound 97C according to the preparation method of compound 7, 18% yield. MS: 380 [M+l]+. 1H NMR (400 MHz, DMSO) δ: 9.26 (s, 1H), 8.90 (d, J = 6.4 Hz, 2H), 8.01 (d, J = 6.4 Hz, 2H) , 7.36 (m, 1H), 3.73 (d, 12.4 Hz, 2H), 3.45 (m, 2H), 3.25 (m, 1H), 2.34 (m, 2H), 2.23 (s, 2H), 2.18 (s, 6H), 2.10-2.14 (m, 2H), 1.06 (s, 9H).
实施例九十八  Example ninety eight
N- (2，6-二甲基 -4- (4-吗啉哌啶） - -苯基） -3,3-二甲基丁酰胺的制备
Figure imgf000088_0002
Preparation of N-(2,6-dimethyl-4-(4-morpholinylpiperidine)-phenyl)-3,3-dimethylbutanamide
Figure imgf000088_0002
4- ( 1- (3,5-二甲基 -4-硝基苯基） -4-哌啶基) 吗啉 (化合物 98A)  4-(1-(3,5-Dimethyl-4-nitrophenyl)-4-piperidinyl)morpholine (Compound 98A)
本品由 4-哌啶基 -4-吗啉和 5-氟 -1,3-二甲基 -2硝基苯按照化合物 83D的制备方法合成， 47%收率。 MS: 320.2 (M+H+).  This product was synthesized from 4-piperidinyl-4-morpholine and 5-fluoro-1,3-dimethyl-2nitrobenzene according to the preparation method of compound 83D, 47% yield. MS: 320.2 (M+H+).
2，6-二甲基 -4- (4-哌啶) -1-苯胺 (化合物 98B)  2,6-Dimethyl-4-(4-piperidinyl)-1-phenylamine (Compound 98B)
本品由化合物 98A和硫代硫酸钠按照化合物 1C的制备方法合成， 得粗品直接投下步反  This product is synthesized from compound 98A and sodium thiosulfate according to the preparation method of compound 1C, and the crude product is directly cast.
N- (2,6-二甲基 -4- (4-吗啉哌啶） -1-苯基） -3,3-二甲基丁酰胺 （化合物 98) 化合物 98B (300 mg， 1 mmol) 与二异丙基乙基胺 （DIEA, 0.5 mL， 3.18 mmol)溶于 20 mL二氯甲烷中， 室温搅拌 30分钟， 之后滴加 3，3-二甲基丁酰胺 （0.6 mL， 4.26 mmol) 后继 续室温搅拌 2 h， 反应完成后， 加入水， 乙酸乙酯萃取， 制备柱分离纯化得化合物 98为白色 固体（60 mg， 15%收率）。 MS: 388.3 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ: 8.57 (brs, 1H)， 6.67 (s， 1H), 3.60-3.64 (m， 4H)， 3.13-3.16 (m， 2H), 2.17 (s， 3H), 1.19-1.29 (m， 12H), 1.05 (s， 4H)， 1.01 (s, 9H). N-(2,6-Dimethyl-4-(4-morpholinylpiperidine)-1-phenyl)-3,3-dimethylbutanamide (Compound 98) Compound 98B (300 mg, 1 mmol) and diisopropylethylamine (DIEA, 0.5 mL, 3.18 mmol) were dissolved in 20 mL dichloromethane and stirred at room temperature for 30 min, then 3,3-dimethyl The butyl amide (0.6 mL, 4.26 mmol) was stirred at room temperature for 2 h. After the reaction was completed, water was added, ethyl acetate was evaporated, and the product was purified to afford compound 98 as a white solid (60 mg, 15% yield). MS: 388.3 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ: 8.57 (brs, 1H), 6.67 (s, 1H), 3.60-3.64 (m, 4H), 3.13-3.16 (m, 2H), 2.17 (s, 3H), 1.19-1.29 (m, 12H), 1.05 (s, 4H), 1.01 (s, 9H).
实施例九十九  Example ninety nine
N- (4- ( 1，4'-联哌啶 -Γ-基） -2,6-二甲基苯） -3,3-二甲基丁酰胺的制备  Preparation of N-(4-(1,4'-bipiperidinyl-fluorenyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000089_0001
Figure imgf000089_0001
1'- (3，5-二甲基-4-硝基苯) -1，4'-联哌啶 （化合物 99A)  1'-(3,5-Dimethyl-4-nitrophenyl)-1,4'-bipiperidine (Compound 99A)
本品由 5-氟 -1,3-二甲基 -2-硝基苯和 1，4'-联哌啶按照化合物 83D的制备方法合成， 57%收 率。  This product was synthesized from 5-fluoro-1,3-dimethyl-2-nitrobenzene and 1,4'-bipiperidine according to the preparation method of compound 83D, 57% yield.
4- ( 1，4'-联哌啶 -Γ-基） -2,6-二甲基苯胺 （化合物 99B)  4-( 1,4'-bipiperidinyl-fluorenyl)-2,6-dimethylaniline (Compound 99B)
本品由化合物 99A按照化合物 1C的制备方法合成， 92%收率。  This product was synthesized from Compound 99A according to the preparation method of Compound 1C, yield of 92%.
N- (4- ( 1，4'-联哌啶 -Γ-基) -2,6-二甲基苯) -3,3-二甲基丁酰胺 （化合物 99)  N-(4-(1,4'-bipiperidin-indenyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (compound 99)
本品由化合物 99B和 3，3-二甲基丁酰氯按照化合物 98的制备方法合成， 21%收率。 MS: 386 (M+H+). 1H NMR (400 MHz, CDC13) δ: 10.99 (brs, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 4.09 (brs, 1H), 3.74-3.72 (d， J = 9.2 Hz, 2H), 3.57-3.55 (d， J = 10.8 Hz, 4H)， 2.89 (s, 2H), 2.64 (s, 2H), 2.35 (s， 2H), 2.28 (s， 8H)， 2.01-1.95 (m， 5H)， 1.40 (brs, 1H), 1.14 (s， 9H). This product was synthesized from Compound 99B and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 98, 21% yield. MS: 386 (M+H+). 1H NMR (400 MHz, CDC1 3 ) δ: 10.99 (brs, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 4.09 (brs, 1H), 3.74- 3.72 (d, J = 9.2 Hz, 2H), 3.57-3.55 (d, J = 10.8 Hz, 4H), 2.89 (s, 2H), 2.64 (s, 2H), 2.35 (s, 2H), 2.28 (s , 8H), 2.01-1.95 (m, 5H), 1.40 (brs, 1H), 1.14 (s, 9H).
实施例一百  Example one hundred
N-(4-( -1-基)哌啶 -1-基) -2，6-二甲基苯) -3，3-二甲基丁酰胺的制备
Figure imgf000089_0002
Preparation of N- (4-(-1-yl)piperidin-1-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000089_0002
1-(3，5-二甲基 -4-硝基苯 )-4- (吡咯烷 -1-基)哌啶 （化合物 100A)  1-(3,5-Dimethyl-4-nitrophenyl)-4-(pyrrolidin-1-yl)piperidine (Compound 100A)
本品由 5-氟 -1,3-二甲基 -2-硝基苯和 4- (吡咯烷 -1-基)哌啶按照化合物 83D的制备方法合 成， 70%收率。  This product was synthesized from 5-fluoro-1,3-dimethyl-2-nitrobenzene and 4-(pyrrolidin-1-yl)piperidine according to the preparation method of Compound 83D in 70% yield.
4- (吡咯烷 -1-基）哌啶 -2,6-二甲基苯胺 （化合物 100B) 本品由化合物 100A按照化合物 1C的制备方法合成， 79%收率。 4-(pyrrolidin-1-yl)piperidine-2,6-dimethylaniline (Compound 100B) This product was synthesized from Compound 100A according to the preparation method of Compound 1C, 79% yield.
N-(4-(4- (吡咯烷 -1-基)哌啶 -1-基) -2,6-二甲基苯 )-3，3-二甲基丁酰胺 （化合物 100) 本品由化合物 100B和 3，3-二甲基丁酰氯按照化合物 98的制备方法合成， 32%收率。 MS: 372 (M+H+). 1H NMR (400 MHz, CDC13) δ: 10.99 (brs, 1H)， 7.23 (s, 1H)， 6.83 (s, 1H)， 3.81-3.76 (m， 5H)， 3.47 (brs, 2H), 3.11 (brs, 3H), 2.52-2.45 (m， 4H)， 2.36 (s， 2H), 2.28 (s， 6H)， 2.18 (s， 4H)， 2.01-1.95 (m, 5H)， 1.40 (brs, 1H), 1.17 (s, 9H). N-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 100) Compound 100B and 3,3-dimethylbutyryl chloride were synthesized according to the procedure for the preparation of compound 98 in 32% yield. MS: 372 (M+H+). 1H NMR (400 MHz, CDC1 3 ) δ: 10.99 (brs, 1H), 7.23 (s, 1H), 6.83 (s, 1H), 3.81-3.76 (m, 5H), 3.47 (brs, 2H), 3.11 (brs, 3H), 2.52-2.45 (m, 4H), 2.36 (s, 2H), 2.28 (s, 6H), 2.18 (s, 4H), 2.01-1.95 (m, 5H), 1.40 (brs, 1H), 1.17 (s, 9H).
实施例一百零一  Example one hundred and one
N- (2，6-二甲基 -4- (2- (4-三氟甲基苯基)吡咯）苯基） -3,3-二甲基丁酰胺 （化合物 101 ) 的制备
Figure imgf000090_0001
Preparation of N-(2,6-dimethyl-4-(2-(4-trifluoromethylphenyl)pyrrole)phenyl)-3,3-dimethylbutanamide (Compound 101)
Figure imgf000090_0001
本品由 2- (4-三氟甲基苯基）吡咯和 N- (4-溴代 -2,6-二甲基苯基） -3， 3-二甲基丁酰胺按 照化合物 7的制备方法合成， 16%收率。 MS: 433.2 [M+H]+。 1H NMR (400 MHz, DMSO- 6) δ: 8.76 (s, 1H)， 7.67 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.12 (s, 2H), 4.85 (d, J = 8.0 Hz, 1H), 3.70 (t， J = 7.2 Hz, 1H), 3.34 (s， 1H), 2.37-2.42 (m， 1H), 2.13 (s， 2H), 1.99 (s， 7H), 1.81-1.83 (m， 2H), 1.16 (s, 9H). This product is prepared from 2-(4-trifluoromethylphenyl)pyrrole and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide according to compound 7. Method synthesis, 16% yield. MS: 433.2 [M+H] + . 1H NMR (400 MHz, DMSO-6) δ: 8.76 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.12 (s, 2H), 4.85 (d, J = 8.0 Hz, 1H), 3.70 (t, J = 7.2 Hz, 1H), 3.34 (s, 1H), 2.37-2.42 (m, 1H), 2.13 (s, 2H), 1.99 (s , 7H), 1.81-1.83 (m, 2H), 1.16 (s, 9H).
实施例一百零二  Example one hundred and two
N-(2，6-二甲基 -4-(4-苯基哌嗪 -1-基)苯基) -3，3-二甲基丁酰胺 （化合物 102) 的制备  Preparation of N-(2,6-dimethyl-4-(4-phenylpiperazin-1-yl)phenyl)-3,3-dimethylbutanamide (Compound 102)
Figure imgf000090_0002
Figure imgf000090_0002
本品由 N- (4-溴 -2,6-二甲基苯基） -3,3-二甲基丁酰胺和 1-苯基哌嗪按照化合物 5的制备 方法合成， 21%收率。 MS: 380.3 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.34-7.29 (m， 1H), 7.01 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.2 Hz 2H), 6.72 (s， 1H), 6.55 (s， 1H), 3.37 (s， 4H)， 3.34 (s， 4H)， 2.30 (s， 2H), 2.47(s, 6H)， 1.04 (s， 9H). This product was synthesized from N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide and 1-phenylpiperazine according to the preparation method of compound 5, 21% yield. MS: 380.3 (M+H+). 1H NMR (400 MHz, CDC1 3 ) δ: 7.34-7.29 (m, 1H), 7.01 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.2 Hz 2H ), 6.72 (s, 1H), 6.55 (s, 1H), 3.37 (s, 4H), 3.34 (s, 4H), 2.30 (s, 2H), 2.47(s, 6H), 1.04 (s, 9H) .
实施例一百零三  Example one hundred and three
N-(2，6-二甲基 -4-(4- (吡啶 -2-基)哌嗪 -1-基)苯) -3，3-二甲基丁酰胺的制备 ,N、 N、Preparation of N-(2,6-dimethyl-4-(4-(pyridin-2-yl)piperazin-1-yl)benzene)-3,3-dimethylbutanamide , N, N,
Figure imgf000091_0001
Figure imgf000091_0001
l- (3，5-二甲基 -4-硝基苯 ) -4- (吡啶 -2-基） 哌嗪 （化合物 103A)  L-(3,5-Dimethyl-4-nitrophenyl)-4-(pyridin-2-yl)piperazine (Compound 103A)
本品由 5-氟 -1,3-二甲基 -2-硝基苯和 1- (吡啶 -2-基）哌嗪按照化合物 83D的制备方法， 120°C 反应 6h合成， 75%收率。  This product is synthesized from 5-fluoro-1,3-dimethyl-2-nitrobenzene and 1-(pyridin-2-yl)piperazine according to the preparation method of compound 83D, reacted at 120 ° C for 6 h, 75% yield .
1- (3,5-二甲基 -4-苯胺） -4- (吡啶 -2-基) 哌嗪 (化合物 103B)  1-(3,5-Dimethyl-4-phenylamine)-4-(pyridin-2-yl)piperazine (Compound 103B)
本品由化合物 103A按照化合物 1C的制备方法合成， 71%收率。  This product was synthesized from Compound 103A according to the method for the preparation of Compound 1C, yield 71%.
N-(2，6-二甲基 -4-(4- (吡啶 -2-基)哌嗪小基)苯) -3,3-二甲基丁酰胺 （化合物 103 )  N-(2,6-Dimethyl-4-(4-(pyridin-2-yl)piperazine) phenyl)-3,3-dimethylbutanamide (Compound 103)
本品由化合物 103B和 3，3-二甲基丁酰氯按照化合物 98的制备方法合成， 27%收率。 MS: 381 (M+H+). 1H NMR (400 MHz, CDC13) δ: 9.25 (brs, 1H), 7.57-7.53 (m, 1H), 6.75-6.71 (m, 4H), 6.54 (s， 1H), 3.71 (s， 4H)， 3.29 (s， 4H)， 2.23 (s， 2H), 2.25 (s， 6H)， 1.17 (s， 9H). This product was synthesized from Compound 103B and 3,3-dimethylbutyryl chloride according to the preparation method of Compound 98, 27% yield. MS: 381 (M+H+). 1H NMR (400 MHz, CDC1 3 ) δ: 9.25 (brs, 1H), 7.57-7.53 (m, 1H), 6.75-6.71 (m, 4H), 6.54 (s, 1H ), 3.71 (s, 4H), 3.29 (s, 4H), 2.23 (s, 2H), 2.25 (s, 6H), 1.17 (s, 9H).
实施例一百零四  Example one hundred and four
N-(2，6-二甲基 -4-(4-(3-(三氟甲基)苯基)哌嗪 -1-基)苯基) -3，3-二甲基丁酰胺盐酸盐 （化合物 104) 的制备  N-(2,6-Dimethyl-4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)phenyl)-3,3-dimethylbutyramide hydrochloride Preparation of salt (compound 104)
Figure imgf000091_0002
Figure imgf000091_0002
本品由 N-(4-溴 -2，6-二甲苯基) -3，3-二甲基丁酰胺和 1- H三氟甲基)苯基)哌嗪盐酸盐按照 化合物 7的制备方法合成， 27% 收率。 MS: 448 [M+l]+. 1H NMR (400 MHz, DMSO) δ: 9.21 (s， 1H), 7.49(t, J= 8.0 Hz, 1H)， 7.18-7.36 (m， 4H)， 7.16 (d, J= 8.8 Hz, 1H)， 3.65 (s， 4H)， 3.53(s, 4H)， 2.22 (s， 2H), 2.16 (s， 6H)， 1.06 (s， 9H). This product is prepared from N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide and 1-H-trifluoromethyl)phenyl)piperazine hydrochloride according to compound 7. Method synthesis, 27% yield. MS: 448 [M+l] + . 1H NMR (400 MHz, DMSO) δ: 9.21. (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.18-7.36 (m, 4H), 7.16 ( d, J = 8.8 Hz, 1H), 3.65 (s, 4H), 3.53(s, 4H), 2.22 (s, 2H), 2.16 (s, 6H), 1.06 (s, 9H).
实施例一百零五  Example one hundred and five
N- (2， 6-二甲基 -4- (4- (4- (三氟甲基） 苯基） 哌嗪小基） 苯基） -3， 3-二甲基丁酰胺 盐酸盐 （化合物 105 ) 的制备
Figure imgf000091_0003
N-(2,6-Dimethyl-4-(4-(4-(trifluoromethyl)phenyl)piperazine) phenyl)-3,3-dimethylbutanamide hydrochloride ( Preparation of compound 105)
Figure imgf000091_0003
本品由 1- (4- (三氟甲基）苯基）哌嗪和 N-(4-溴 -2,6-二甲苯基) -3,3-二甲基叔丁酰胺按照 化合物 7的制备方法合成， 35%收率。 MS: 448.3 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H)， 7.54( d, J = 8.8 Hz, 2H)， 7.14 (d，J = 8.8 Hz, 2H)， 6.71 (s, 2H), 3.41-3.43 (m， 4H)， 3.23-3.26 (m， 4H)， 2.18 (s， 2H), 2.11 (s， 6H)， 1.06 (s， 9H). This product consists of 1-(4-(trifluoromethyl)phenyl)piperazine and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-tert-butanamide according to compound 7 Preparation method Synthesis, 35% yield. MS: 448.3 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 7.54 ( d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 6.71 (s, 2H), 3.41-3.43 (m, 4H), 3.23-3.26 ( m, 4H), 2.18 (s, 2H), 2.11 (s, 6H), 1.06 (s, 9H).
实施例一百零六  Example one hundred and six
N-(4-(2-氟 -6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000092_0001
N-(4-(2-Fluoro-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-di Preparation of methylbutyric acid
Figure imgf000092_0001
6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-甲酸叔丁酯 （化合物 106A)  6,7-Dihydrothiophene [3,2-c]pyridine -5(4H)-carboxylic acid tert-butyl ester (Compound 106A)
4，5，6，7-四氢噻吩 [3，2-c]口比啶 (2 g， 14.4 mmol)和三乙胺（7.5 mL， 57.6 mmol)溶于 50 mL 二氯甲烷后， 于 0 °〇加入二叔丁基二甲酸酐 （3.76 g， 17.2 mmol), 反应液室温搅拌 30 min 后， 减压旋干溶剂， 剩余物水洗， 乙酸乙酯萃取， 石油醚： 乙酸乙酯 =10: 1分离纯化得目标物 为液体 （3.5 g， 99%收率）。 MS: 184.1 (M+H+).  4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (2 g, 14.4 mmol) and triethylamine (7.5 mL, 57.6 mmol) dissolved in 50 mL of dichloromethane, at 0 After adding di-tert-butyldicarboxylic anhydride (3.76 g, 17.2 mmol), the reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated, evaporated, evaporated, evaporated. 1 The target was isolated and purified as a liquid (3.5 g, 99% yield). MS: 184.1 (M+H+).
2-氟 -6,7-二氢噻吩 [3，2-c]吡啶 -5C4H)-甲酸叔丁酯 （化合物 106B)  2-Fluoro-6,7-dihydrothiophene [3,2-c]pyridine -5C4H)-carboxylic acid tert-butyl ester (Compound 106B)
化合物 106A ( 1.5 g, 6.28 mmol) 溶于 90 mL无水四氢呋喃后降温至 -78 。C , 滴加正丁 基锂（1.6 M, 5.1 mL, 8.16 mmol)后继续搅拌 1 h。 -78 °C滴加 N-氟 -N- (苯磺酰基）苯磺酰 胺（2.38 g， 7.54 mmol) 10 mL的四氢呋喃溶液， 滴加完成后， 反应液升至室温继续搅拌 8 h， 滴加水， 乙酸乙酯萃取， 石油醚： 乙酸乙酯 =5: 1分离纯化得目标物为液体（0.8 g， 50%收率）。 MS: 202.1 (M+H+).  Compound 106A (1.5 g, 6.28 mmol) was dissolved in 90 mL of dry tetrahydrofuran and then cooled to -78. C. Add n-butyllithium (1.6 M, 5.1 mL, 8.16 mmol) dropwise and continue stirring for 1 h. N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.38 g, 7.54 mmol) 10 mL of tetrahydrofuran solution was added dropwise at -78 °C. After the dropwise addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 8 h. , ethyl acetate extraction, petroleum ether: ethyl acetate = 5: 1 was isolated and purified to give a liquid (0.8 g, 50% yield). MS: 202.1 (M+H+).
2-氟 -4，5，6，7-四氢噻吩 [3，2-c]吡啶三氟乙酸盐 （化合物 106C)  2-fluoro-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine trifluoroacetate (compound 106C)
化合物 106B (275 mg, 1 mmol)溶于 5 mL二氯甲烷后， 于 0 °C加入三氟乙酸（5 mL)， 反应液室温搅拌 30 min后， 减压旋干溶剂， 所得物直接用于下一步反应 （275 mg， 100%收 率）。 MS: 158.1 (M+H+).  After compound 106B (275 mg, 1 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 30 min. The next reaction (275 mg, 100% yield). MS: 158.1 (M+H+).
N-(4-(2-氟 -6,7-二氢噻吩 [3，2-c]吡啶 -5(4H) -基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化合 物 106)  N-(4-(2-Fluoro-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-di Methyl butyramide (compound 106)
化合物 106C (275 mg, 1 mmol)、 Pd2(dba)3 ( 140 mg, 0.2 mmol) X-phos ( 95 mg, 0.2 mmol)、 N- ( 4-溴 -2,6-二甲基苯基） -3，3-二甲基丁酰胺（ 327 mg， 1.1 mmol )及叔丁醇钾（ 448 mg， 4 mmol ) 溶于 40 mL甲苯中， 反应液于封管中 120°C反应 8 h， 反应完成后， 过滤除去固体， 减压旋干 滤液， 剩余物制备柱分离纯化得目标化合物， 为黄色固体 （60 mg， 15% 收率）。 MS: 375.2 (M+H+).1H NMR (400 MHz, CDC13) δ: 6.72 (s, 2H), 6.22 (s, 1H), 4.14 (s, 2H), 3.58-3.60 (m, 2H),2.83 (s， 2H), 2.30 (s， 2H), 2.24 (s， 6H)， 1.16 (s, 9H). 实施例一百零七 Compound 106C (275 mg, 1 mmol), Pd 2 (dba) 3 (140 mg, 0.2 mmol) X-phos (95 mg, 0.2 mmol), N-(4-bromo-2,6-dimethylphenyl) -3,3-dimethylbutyramide (327 mg, 1.1 mmol) and potassium tert-butoxide (448 mg, 4 mmol) were dissolved in 40 mL of toluene, and the reaction was reacted at 120 ° C for 8 h in a sealed tube. After completion of the reaction, the solid was removed by filtration, and the filtrate was evaporated to dryness, and the residue was purified to give the title compound as a yellow solid (60 mg, 15% yield). MS: 375.2 (M+H + ).1H NMR (400 MHz, CDC1 3 ) δ: 6.72 (s, 2H), 6.22 (s, 1H), 4.14 (s, 2H), 3.58-3.60 (m, 2H) , 2.83 (s, 2H), 2.30 (s, 2H), 2.24 (s, 6H), 1.16 (s, 9H). Example one hundred and seven
N- 4-(2-氯 -6,7-四氢噻吩 [3，2-C]吡啶 -5(4H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺的制备
Figure imgf000093_0001
N- 4-(2-chloro-6,7-tetrahydrothiophene[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethyl Preparation of butylbutyramide
Figure imgf000093_0001
2-氯 -4，5，6，7-四氢噻吩 [3，2-c]吡啶 （化合物 107A)  2-Chloro-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (Compound 107A)
4，5，6，7-四氢噻吩并 [3.2-c]吡啶 （40 g， 227.7 mmol) 溶于乙腈 （300 mL)， N-氯代二乙酰亚 胺 (33.4 g， 250.5 mmol) 分批加入上述溶液中。 室温下搅拌 7小时， 加入水 （lOO mL) 淬灭反 应， 加入饱和的碳酸氢钠溶液中和至中性， 乙酸乙酯萃取， 有机相用饱和的食盐水洗涤， 无 水硫酸钠干燥， 旋干后得目标产物直接用于下一步反应 （35 g， 收率 87%)。  4,5,6,7-tetrahydrothieno[3.2-c]pyridine (40 g, 227.7 mmol) in acetonitrile (300 mL), N-chlorodiethylimide (33.4 g, 250.5 mmol) Add to the above solution. Stir at room temperature for 7 hours, add water (100 mL) to quench the reaction, add saturated sodium bicarbonate solution, neutralize to neutral, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate After drying, the target product was directly used for the next reaction (35 g, yield 87%).
2-氯 -5-(3，5-二甲基 -4-硝基苯基) -4，5，6，7-四氢噻吩 [3，2-c]吡啶 （化合物 107B)  2-Chloro-5-(3,5-dimethyl-4-nitrophenyl)-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (Compound 107B)
在 150°C下， 将 2-氯 -4，5，6，7-四氢噻吩 [3，2-c]吡啶 (35 g， 202.3 mmol), 5-氟 -1,3-二甲基 -2- 硝基苯 （34 g， 202.31 mmol)和碳酸钾 (83.9 g， 607.0 mmol)在 N-甲基吡咯烷酮 (300 mL)中搅拌 24小时。 向该反应液中加入乙酸乙酯 (500 mL)和水 (200 mL)， 有机相分离， 饱和的食盐水洗 涤， 无水硫酸钠干燥， 旋干得到粗产品， 粗产品用二氯甲烷和正己烷重结晶后得到目标产物 (21 g，收率 32%)。  2-Chloro-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (35 g, 202.3 mmol), 5-fluoro-1,3-dimethyl- at 150 ° C 2-Nitrobenzene (34 g, 202.31 mmol) and potassium carbonate (83.9 g, 607.0 mmol) were stirred in N-methylpyrrolidone (300 mL) for 24 hours. Ethyl acetate (500 mL) and water (200 mL) were added to the mixture, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The title product (21 g, yield 32%) was obtained after crystals from crystals.
4-(2-氯 -6,7-四氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯胺 （化合物 107C)  4-(2-Chloro-6,7-tetrahydrothiophene [3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (Compound 107C)
2-氯 -5-(3，5-二甲基 -4-硝基苯基) -4，5，6，7-四氢噻吩 [3，2-c]吡啶 (21 g， 65.05 mmol)和保险粉 (90 g， 520.4 mmol)在甲醇和水 (10/1， 400 mL)的混合溶液中搅拌回流过夜。 旋转蒸干大部分溶 剂， 加入乙酸乙酯 (500 mL)和水 (200 mL)， 有机相分离， 用饱和的食盐水洗涤， 无水硫酸钠干 燥， 旋转蒸干后得到目标产物 (18 g， 94% 收率)。  2-chloro-5-(3,5-dimethyl-4-nitrophenyl)-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (21 g, 65.05 mmol) and The powder (90 g, 520.4 mmol) was stirred and refluxed overnight in a mixture of methanol and water (10/1, 400 mL). The solvent was evaporated to dryness. EtOAc (EtOAc) (EtOAc) 94% yield).
N-(4-(2-氯 -6,7-四氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺（化合物 N-(4-(2-chloro-6,7-tetrahydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-di Methyl butyramide
107) 107)
4-(2-氯 -6,7-四氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯胺 (18 g， 61.46 mmol)溶液二氯甲 烷 (500 mL)， 加入三乙胺 (12.8 mL， 92.19 mmol)后搅拌半个小时， 3,3-二甲基丁酰氯 (10.2 mL， 93.76 mmol)逐滴的加入到上述溶液中， 常温下搅拌 2小时， 波层色谱检测无起始原料， 加入 水淬灭， 二氯甲烷萃取， 有机相用饱和的食盐水洗涤， 无水硫酸钠干燥， 旋干， 粗产品用乙 腈重结晶， 得到白色的目标产物 (17 g， 收率 71% )。 MS: 391.3 (M+H+).1H NMR (400 MHz, DMSO) δ: 8.91 (s, 1H), 6.93 (s, 1H), 6.72 (s, 2H), 4.17 (s, 2H), 3.56 (t，J= 5.6 Hz, 2H)， 2.82 (t，J= 5.2 Hz, 2H), 2.17 (s， 2H), 2.10 (s， 6H)， 1.05 (s， 9H). 4-(2-Chloro-6,7-tetrahydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (18 g, 61.46 mmol) methylene chloride (500 mL), add triethylamine (12.8 mL, 92.19 mmol), stir for half an hour, add 3,3-dimethylbutyryl chloride (10.2 mL, 93.76 mmol) dropwise to the above solution, stir at room temperature. After 2 hours, no starting material was detected by layer chromatography, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. Target product (17 g, yield 71%). MS: 391.3 (M+H + ).1H NMR (400 MHz, DMSO) δ: 8.91 (s, 1H), 6.93 (s, 1H), 6.72 (s, 2H), 4.17 (s, 2H), 3.56 ( t, J = 5.6 Hz, 2H), 2.82 (t, J = 5.2 Hz, 2H), 2.17 (s, 2H), 2.10 (s, 6H), 1.05 (s, 9H).
实施例一百零八 N-(4- (2善 6， 7-二氢噻吩 [3， 2-c]吡啶 -5 (4H) -基) -2, 6-二甲基苯) -3， 3-二甲基丁酰 的制备
Figure imgf000094_0001
Example one hundred and eight N-(4-(2,6-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl Preparation of acyl
Figure imgf000094_0001
2-溴 -4，5，6，7-四氢噻吩 [3，2，-c]吡啶 （化合物 108A)  2-Bromo-4,5,6,7-tetrahydrothiophene [3,2,-c]pyridine (Compound 108A)
4，5，6，7-四氢噻吩 [3，2，-c]口比啶 ( lg, 7.1 mmol) 溶于 30ml二氯甲烷 /水 =1 : 1溶液中， 缓慢 滴加溴 （1.12 g，7.1 mmol) 的二氯甲烷溶液。 滴加完毕， 室温搅拌反应 30分钟。 反应结束， 用异丙醇 /氯仿 =1 : 5的有机溶剂提取三次， 合并有机层， 用无水硫酸钠干燥， 浓縮， 得到粗 品化合物 108A ( l g，67%收率）， 直接用于下一步反应。  4,5,6,7-tetrahydrothiophene [3,2,-c]pyridinium ( lg, 7.1 mmol) dissolved in 30 ml of dichloromethane / water = 1 : 1 solution, slowly added bromine (1.12 g) , 7.1 mmol) in dichloromethane. After the dropwise addition was completed, the reaction was stirred at room temperature for 30 minutes. After the reaction was completed, the organic layer was extracted with EtOAc EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHH One step reaction.
2-溴 -5- ( 3， 5-二甲基 -4-硝基苯） 4，5，6，7-四氢噻吩 [3，2，-c]卩比啶 （化合物 108B)  2-bromo-5-(3,5-dimethyl-4-nitrophenyl) 4,5,6,7-tetrahydrothiophene [3,2,-c]indolepyridinium (Compound 108B)
化合物 108A ( 500 mg, 2.3 mmol), 5-氟 -1， 3-二甲基 -2-硝基苯 （428 mg， 2.53 mmol) 禾口 碳酸钾（952 mg， 6.9 mmol)溶于 DMF中， 封管 150°C反应 48小时。 反应结束， 冷却到室温， 加入水， 乙酸乙酯提取， 有机层用无水硫酸钠干燥， 浓縮。 粗品经硅胶柱层析提纯， 石油醚 / 乙酸乙酯 -10: 1洗脱得产物 （460 mg， 55%收率）。  Compound 108A (500 mg, 2.3 mmol), 5-fluoro-1,3-dimethyl-2-nitrobenzene (428 mg, 2.53 mmol) and potassium carbonate (952 mg, 6.9 mmol) dissolved in DMF. The tube was sealed at 150 ° C for 48 hours. After the reaction was completed, the mixture was cooled to room temperature. The crude product was purified by EtOAc EtOAc elut elut elut elut
4- (2-溴 -6,7-二氢噻吩 [3，2，-c]吡啶 -5 (4H) -基) -2, 6-二甲基苯胺 (化合物 108C ) 化合物 108B (460 mg， 1.26 mmol)和连二亚硫酸钠（ 1.8 g， 10.08 mmol)溶于甲醇 /水 =10: 1的溶液中， 80°C封管反应 12小时。 反应结束， 冷却至室温， 过滤， 浓縮除去甲醇。 加入水， 乙酸乙酯提取， 有机层用无水硫酸钠干燥， 浓縮。 粗品化合物 108C ( 300 mg， 70%收率） 直 接用于下一步反应。  4-(2-Bromo-6,7-dihydrothiophene[3,2,-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (Compound 108C) Compound 108B (460 mg, 1.26 mmol) and sodium dithionite (1.8 g, 10.08 mmol) were dissolved in a solution of methanol/water = 10:1, and the reaction was sealed at 80 ° C for 12 hours. The reaction was completed, cooled to room temperature, filtered and concentrated to remove methanol. Water was added, and ethyl acetate was evaporated. The crude compound 108C (300 mg, 70% yield) was used directly in the next step.
N-(4- (2善 6， 7-二氢噻吩 [3， 2-c]吡啶 -5 (4H) -基) -2, 6-二甲基苯) 3， 3-二甲基丁酰 胺 （化合物 108 )  N-(4-(2,6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl) 3,3-dimethylbutanamide (compound 108)
本品由化合物 108C按照化合物 107的制备方法合成， 78%收率。 MS: 437.2 (M+H+).1H NMR (400 MHz, DMSO-d6) δ: 8.90 (s， 1H), 7.03 (s， 2H), 6.70 (s， 2H), 6.28 (s， 2H), 4.18 (s， 2H), 3.54 (m， 2H), 2.81 (m， 2H), 2.17 (s， 2H), 2.10 (s， 6H)， 1.05(s, 9H). This product was synthesized from Compound 108C according to the preparation method of Compound 107, 78% yield. MS: 437.2 (M+H + ).1H NMR (400 MHz, DMSO-d6) δ: 8.90 (s, 1H), 7.03 (s, 2H), 6.70 (s, 2H), 6.28 (s, 2H), 4.18 (s, 2H), 3.54 (m, 2H), 2.81 (m, 2H), 2.17 (s, 2H), 2.10 (s, 6H), 1.05(s, 9H).
实施例一百零九  Example one hundred and nine
N-(2， 6-二甲基 -4- (2-甲基 -6， 7-二氢噻吩 [3， 2-c]吡啶 -5 (4H) -基) 苯基) -3， 3-二甲基 丁酰胺 （化合物 109) 的制备
Figure imgf000094_0002
N-(2， 6-二甲基 -4- (2善 6， 7-二氢噻吩 [3， 2-c]吡啶 -5 (4H) -基) 苯基) -3， 3-二甲基丁 酰胺（300 mg， 0.69 mmol), 三甲基环三硼氧烷（347 mg， 2.76 mmol), 四 （三苯基磷）钯（81 mg, 0.069 mmol)和碳酸钾 （286 mg， 2.07 mmol)溶于 1,4-二氧六环中， 氮气保护下回流反应 12小时。 反应结束， 冷却至室温， 过滤， 浓縮滤液， 然后溶于乙酸乙酯中， 用水洗涤。 有机 层用无水硫酸钠干燥， 浓縮。粗品经高效液相制备得到化合物 109 (200 mg, 32%收率）。 MS: 371.3 (M+H+).1H NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1H), 6.83 (s, 2H), 6.59 (s, 1H), 4.20 (s， 2H), 3.60 (m， 2H), 2.87 (m， 2H), 2.40 (s， 3H), 2.25 (s， 2H), 2.12 (s， 6H)， 1.05(s, 9H). N-(2,6-Dimethyl-4-(2-methyl-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)phenyl)-3, 3- Preparation of dimethylbutyramide (compound 109)
Figure imgf000094_0002
N-(2,6-Dimethyl-4-(2,6-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)phenyl)-3,3-dimethyl Butanamide (300 mg, 0.69 mmol), trimethylcyclotriborane (347 mg, 2.76 mmol), tetrakis(triphenylphosphine)palladium (81 mg, 0.069 mmol) and potassium carbonate (286 mg, 2.07 mmol) Dissolved in 1,4-dioxane and refluxed under nitrogen for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated. The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude product was purified by HPLC to give compound 109 (200 mg, 32% yield). MS: 371.3 (M+H + ).1H NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1H), 6.83 (s, 2H), 6.59 (s, 1H), 4.20 (s, 2H), 3.60 (m, 2H), 2.87 (m, 2H), 2.40 (s, 3H), 2.25 (s, 2H), 2.12 (s, 6H), 1.05(s, 9H).
实施例一百一" h  Example one hundred one"h
N- (2，6-二甲基 -4- (2- (三氟甲基) -6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) 苯基） -3,3- 二甲基叔丁氧羰基胺盐酸盐的制备  N-(2,6-Dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)phenyl) Preparation of 3,3-dimethyl-tert-butoxycarbonylamine hydrochloride
Figure imgf000095_0001
Figure imgf000095_0001
2-碘 -N-叔丁氧羰基 -4，5，6，7-四氢噻吩 [3，2-c]吡啶 （化合物 110A)  2-iodo-N-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (Compound 110A)
将 6,7-二氢噻吩 [3，2-c]吡啶 -5(4H)-甲酸叔丁酯 （2.60 g， 0.011 mmol) 溶于 50 mL 四氢呋 喃溶液中， 0 °C下加入 N-碘代琥珀酰亚胺 （4.95g， 0.022 mmol )。 闭光室温搅拌过夜。 加入饱 和氯化钠水溶液， 乙酸乙酯萃取， 合并， 干燥， 经石油醚 /乙酸乙酯 =10/1 过柱分离纯化得目 标产物 (3.98g, 99% 收率） MS: 310.0 (M+H+-56).  6,7-Dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (2.60 g, 0.011 mmol) was dissolved in 50 mL of tetrahydrofuran solution, and N-iodo was added at 0 °C. Succinimide (4.95 g, 0.022 mmol). The mixture was stirred at room temperature overnight. Add saturated aqueous sodium chloride solution, extract with EtOAc, EtOAc (EtOAc)EtOAc. -56).
2-三氟甲基 -N-叔丁氧羰基 -4，5，6，7-四氢噻吩 [3，2-C]吡啶 （化合物 110B) 2-trifluoromethyl-N-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiophene [3,2- C ]pyridine (Compound 110B)
将化合物 110A (300 mg, 0.82 mmol)溶于 5 mL N-甲基吡硌烷酮和 5 mL N，N-二甲基甲酰 胺的混合溶液中，氮气保护下， 依次加入碘化亚铜（171 mg， 0.90 mmol), 3，4，7，8-四甲基 -1,10- 菲啰啉（253 mg， 1.07 mmol), 三氟甲基三氟硅烷（583 mmol, 4.10 mmol)和氟化钾 （105 mg， 1.80 mmol), 80°C氮气保护过夜。 加入饱和氯化钠水溶液， 乙酸乙酯萃取， 合并， 干燥， 浓 縮得粗品化合物 110B, 未经纯化， 直接用于下一步反应。 MS: 308.1 (M+H+). Compound 110A (300 mg, 0.82 mmol) was dissolved in a mixed solution of 5 mL of N-methylpyrrolidone and 5 mL of N,N-dimethylformamide under the protection of nitrogen, followed by the addition of cuprous iodide ( 171 mg, 0.90 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (253 mg, 1.07 mmol), trifluoromethyltrifluorosilane (583 mmol, 4.10 mmol) and fluoro Potassium (105 mg, 1.80 mmol) was incubated overnight at 80 °C under nitrogen. A saturated aqueous solution of sodium chloride was added, and ethyl acetate was evaporated and evaporated. MS: 308.1 (M+H + ).
2-三氟甲基 -4，5，6，7-四氢噻吩 [3，2-c]吡啶 （化合物 110C)  2-trifluoromethyl-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (Compound 110C)
将化合物 110B( 252 mg， 0.82 mmol)溶于 10 mL二氯甲烷溶液中，加入三氟乙酸（280 mg， 2.46 mmol), 室温搅拌 2小时。 减压旋除二氯甲烷和三氟乙酸， 水洗， 干燥， 浓縮的粗品化 合物 110C。 MS: 208.0 (M+H+). N- (2，6-二甲基 -4- (2- (三氟甲基) -6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) 苯基） -3,3- 二甲基叔丁氧羰基胺盐酸盐 （化合物 110) Compound 110B (252 mg, 0.82 mmol) was dissolved in 10 mL dichloromethane dichloromethane. The dichloromethane and trifluoroacetic acid were evaporated under reduced pressure, washed with water, and then evaporated and evaporated. MS: 208.0 (M+H + ). N-(2,6-Dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)phenyl) 3,3-dimethyl-tert-butoxycarbonylamine hydrochloride (Compound 110)
氮气保护下， 将三 (二亚苄基丙酮)二钯（0) (55 mg, 0.06 mmol)和 4，5-双 (二苯基膦) -9,9- 二甲基氧杂蒽（Xantphos, 170 mg, 0.82 mmol)溶于 15 mL 的甲苯溶液中搅拌 15分钟， 然后 向溶液中依次加入化合物 110C ( 154 mg, 0.67 mmol), N- (4-溴 -2,6-二甲基苯基） -3,3-二甲基 叔丁基甲基酰胺（292 mg, 0.98 mmol)和叔丁醇钾（367 mg, 3.28mmol)。反应液加热至 120 °C 搅拌过夜。旋除溶剂，粗品经制备分离，用盐酸***溶液酸化得其盐酸盐，为白色固体（18mg， 5%收率）。 MS: 448.3 (M+H+)。 i i NMR (400 MHz, DMSO-d6) δ: 8.93 (s， 1H), 7.54 (d, J = 8.8 Hz, 2H)， 7.14 (d，J = 8.8 Hz, 2H)， 6.71 (s, 2H), 3.41-3.43 (m， 4H)， 3.23-3.26 (m， 4H)， 2.18 (s, 2H), 2.11 (s， 6H)， 1.06 (s, 9H).  Tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.06 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxene (Xantphos) under nitrogen protection , 170 mg, 0.82 mmol) was dissolved in 15 mL of toluene and stirred for 15 minutes. Then, compound 110C (154 mg, 0.67 mmol), N-(4-bromo-2,6-dimethylbenzene) was added to the solution. -3,3-Dimethyl-tert-butylmethylamide (292 mg, 0.98 mmol) and potassium t-butoxide (367 mg, 3.28 mmol). The reaction solution was heated to 120 ° C and stirred overnight. The solvent was evaporated and the crude was purified eluted eluted elut elut elut elut elut elut MS: 448.3 (M+H+). Ii NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 6.71 (s, 2H), 3.41-3.43 (m, 4H), 3.23-3.26 (m, 4H), 2.18 (s, 2H), 2.11 (s, 6H), 1.06 (s, 9H).
实施例一百一" I ^一  Example one hundred one "I ^ one
N-(4- (2-氰基 -6， 7-二氢噻吩 [3， 2-c]吡啶 -5 (4H) -基) -2, 6-二甲基苯) -3， 3-二甲基丁 酰胺 （化合物 111 ) 的制备
Figure imgf000096_0001
N-(4-(2-Cyano-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3, 3-di Preparation of methylbutyricamide (compound 111)
Figure imgf000096_0001
N-(4- (2善 6， 7-二氢噻吩 [3， 2-c]吡啶 -5 (4H) -基) -2, 6-二甲基苯) -3， 3-二甲基丁酰 胺（200 mg, 0.48 mmol),氰化锌（ 168 mg, 0.12 mmol)和四（三苯基磷）钯（56 mg, 0.048 mmol) 溶于四氢呋喃中， 130°C搅拌反应 2小时。 反应结束， 冷却至室温， 加入水， 乙酸乙酯提取， 有机层用无水硫酸镁干燥， 浓縮。 粗品经高效液相制备得到化合物 111 (50 mg, 29%收率）。 MS: 382.2 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 8.97 (s, 1H), 7.78 (s, 1H), 6.70 (s, 2H), 6.28 (s, 2H), 3.57 (m, 2H), 2.98 (m, 2H), 2.17 (s, 2H), 2.10 (s, 6H)， 1.05(s, 9H). N-(4-(2,6-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyl The amide (200 mg, 0.48 mmol), zinc cyanide (168 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (56 mg, 0.048 mmol) were dissolved in tetrahydrofuran and stirred at 130 ° C for 2 hours. After completion of the reaction, the mixture was cooled to EtOAc. The crude product was purified by HPLC to give compound 111 (50 mg, 29% yield). MS: 382.2 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 8.97 (s, 1H), 7.78 (s, 1H), 6.70 (s, 2H), 6.28 (s, 2H), 3.57 (m, 2H), 2.98 (m, 2H), 2.17 (s, 2H), 2.10 (s, 6H), 1.05(s, 9H).
实施例一百一" h二  Embodiment one hundred one" h two
N-(4- (3-溴 -，6，7-二氢噻唑 [3，2-c]吡啶 -5 (4H) -) -2,6-二甲基苯基) -3,3-二甲基丁酰胺的制 备  N-(4-(3-bromo-,6,7-dihydrothiazole[3,2-c]pyridine-5(4H)-)-2,6-dimethylphenyl)-3,3-di Preparation of methylbutyric acid
Figure imgf000096_0002
Figure imgf000096_0002
2，3-二溴 -4，5，6，7-四氢噻唑 [3，2-c]吡啶 （化合物 112A) 4，5，6，7-四氢噻吩 [3，2-c]口比啶 （0.55 g， 3.95 mmol) 溶于 50 mL二氯甲烷后， 于 0 °C批次 加入三氯化铝 （1.05 g， 7.9 mmol), 搅拌 lO min后， 溴素 （0.23 mL， 3.95 mmol), 的 20 mL 二氯甲烷溶液于 0 °0滴加到反应中， 反应液继续室温搅拌 8 h， 饱和氯化铵水溶液洗涤， 乙 酸乙酯萃取， 有机相减压旋干， 二氯甲烷： 甲醇 =10:1分离纯化得目标物为液体（0.25 g， 21% 收率）。 MS: 297.9 (M+H+). 2,3-dibromo-4,5,6,7-tetrahydrothiazole [3,2-c]pyridine (Compound 112A) 4,5,6,7-Tetrahydrothiophene [3,2-c]pyridinium (0.55 g, 3.95 mmol) After dissolving in 50 mL of dichloromethane, a solution of aluminum trichloride (1.05) was added in batches at 0 °C. g, 7.9 mmol), after stirring for 10 min, a solution of bromine (0.23 mL, 3.95 mmol) in 20 mL of dichloromethane was added dropwise at 0 ° 0, and the mixture was stirred at room temperature for 8 h, saturated ammonium chloride The aqueous solution was washed, ethyl acetate was extracted, and the organic phase was evaporated to dryness, methylene chloride: methanol = 10:1, and purified to afford liquid (0.25 g, 21% yield). MS: 297.9 (M+H + ).
2，3-二溴 -6,7-二氢噻唑 [3，2-c]吡啶 -5 (4H) -甲酸叔丁酯 （化合物 112B)  2,3-dibromo-6,7-dihydrothiazole [3,2-c]pyridine -5 (4H)-carboxylic acid tert-butyl ester (Compound 112B)
本品由化合物 112B按照化合物 106A的制备方法合成， 87%收率。 MS: 383.0 (M+H+).This product was synthesized from Compound 112B according to the preparation method of Compound 106A, with a yield of 87%. MS: 383.0 (M+H + ).
3-溴 -6,7-二氢噻唑 [3，2-c]吡啶 -5 (4H) -甲酸叔丁酯 （化合物 112C) 3-bromo-6,7-dihydrothiazole [3,2-c]pyridine -5 (4H)-carboxylic acid tert-butyl ester (Compound 112C)
化合物 112B (0.28 g， 0.73 mmol)溶于 20 mL四氢呋喃后， 于 -78 °C滴入正丁基锂 （1.6 M, 0.5 mL, 0.8 mmol), 反应液继续搅拌 30 min后， 于 -78 °C滴入水 （5 mL) 缓慢升至室温， 反应液饱和氯化铵水洗， 乙酸乙酯萃取， 石油醚： 乙酸乙酯 =10:1 分离纯化得目标物为液体 (0.18 g， 78%收率）。 MS: 264.0 (M+H+).  After compound 112B (0.28 g, 0.73 mmol) was dissolved in 20 mL of tetrahydrofuran, n-butyllithium (1.6 M, 0.5 mL, 0.8 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred for 30 min at -78 ° C dripping into water (5 mL), slowly rising to room temperature, the reaction solution was washed with saturated aqueous ammonium chloride, extracted with ethyl acetate, petroleum ether: ethyl acetate = 10:1, and purified to obtain a liquid (0.18 g, 78%. rate). MS: 264.0 (M+H+).
3-溴 -4，5，6，7-四氢噻唑 [3，2-c]吡啶三氟乙酸盐 （化合物 112D)  3-bromo-4,5,6,7-tetrahydrothiazole [3,2-c]pyridine trifluoroacetate (Compound 112D)
本品由化合物 112C按照化合物 106C的制备方法合成， 85%收率。  This product was synthesized from Compound 112C according to the method for the preparation of Compound 106C, yield of 85%.
3-溴 -5-(3，5-二甲基 -4-硝基苯 )-4，5，6，7-四氢噻唑 [3，2-c]吡啶 （化合物 112E)  3-bromo-5-(3,5-dimethyl-4-nitrobenzene)-4,5,6,7-tetrahydrothiazole [3,2-c]pyridine (Compound 112E)
本品由化合物 112D按照化合物 108B的制备方法合成， 49%收率。 MS: 264.0 (M+H+).This product was synthesized from Compound 112D according to the preparation method of Compound 108B, 49% yield. MS: 264.0 (M+H + ).
4- (3-溴 -，6，7-二氢噻唑 [3，2-c]吡啶 -5 (4H) -) -2,6-二甲基苯胺 （化合物 112F) 化合物 112E (470 mg， 1.28 mmol) 与硫代硫酸钠 （2.23 g， 12.8 mmol) 溶于 30 mL甲 醇及 10 mL水中， 于封管中 90 °C反应 8小时， 反应完成后， 过滤除去固体， 滤液经减压蒸 干后， 得到化合物 112F, 直接用于下一步反应 （450 mg， 100%收率） 。 MS: 335.1 (M+H+). 4-(3-Bromo-,6,7-dihydrothiazole[3,2-c]pyridine-5(4H)-)-2,6-dimethylaniline (Compound 112F) Compound 112E (470 mg, 1.28 Methyl acetate and sodium thiosulfate (2.23 g, 12.8 mmol) were dissolved in 30 mL of methanol and 10 mL of water, and reacted at 90 °C for 8 hours in a sealed tube. After completion of the reaction, the solid was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. , Compound 112F was obtained and used directly in the next step (450 mg, 100% yield). MS: 335.1 (M+H + ).
N-(4- (3-溴 -，6，7-二氢噻唑 [3，2-c]吡啶 -5 (4H) -) -2,6-二甲基苯基) -3,3-二甲基丁酰胺 （化 合物 112)  N-(4-(3-bromo-,6,7-dihydrothiazole[3,2-c]pyridine-5(4H)-)-2,6-dimethylphenyl)-3,3-di Methyl butyramide (compound 112)
本品由化合物 112F按照化合物 107的制备方法合成， 9%收率。 MS: 437.1 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 8.93 (s, 1H), 7.56 (s, 1H), 6.73 (s, 2H), 4.07 (s, 2H), 2.92 (t, J = 5.2 Hz, 2H), 2.18 (s， 2H), 2.11 (s， 6H)， 1.06 (s， 9H). This product was synthesized from Compound 112F according to the preparation method of Compound 107, 9% yield. MS: 437.1 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 8.93 (s, 1H), 7.56 (s, 1H), 6.73 (s, 2H), 4.07 (s, 2H), 2.92 (t, J = 5.2 Hz, 2H), 2.18 (s, 2H), 2.11 (s, 6H), 1.06 (s, 9H).
实施例一百一" h三  Embodiment one hundred one "h three
N- (2，6-二甲基 -4- ( 3-甲基 -6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) ) -苯基) 3，3-二甲基丁酰胺 的制备
Figure imgf000098_0001
N-(2,6-Dimethyl-4-(3-methyl-6,7-dihydrothiophene[3,2-c]pyridine-5(4H))-phenyl) 3,3-dimethyl Preparation of butylbutyramide
Figure imgf000098_0001
3-甲基 -6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -甲酸叔丁酯 （化合物 113A)  3-methyl-6,7-dihydrothiophene [3,2-c]pyridine -5 (4H)-carboxylic acid tert-butyl ester (Compound 113A)
3-溴 -6,7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -甲酸叔丁酯（80 mg， 0.25 mmol ) Pd (PPh3)4 (58 mg, 0.05 mmol) 碳酸钾 （104 mg， 0.75 mmol) 溶于 7 mL二氧六环中， 通入 N2 10 min后， 使用注射器加入三甲基环三硼氧烷 （0.25 mL， 1 mmol), 反应液于封管中 120°C反应 4 h， 反 应完成后， 过滤除去固体， 减压旋干滤液， 剩余物石油醚： 乙酸乙酯 =10:1分离纯化得目标化 合物 （0.1 g， 100% 收率） 。 MS: 198.1 (M+H+). tert-Butyl 3-bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylate (80 mg, 0.25 mmol) Pd (PPh 3 ) 4 (58 mg, 0.05 mmol) Potassium (104 mg, 0.75 mmol) was dissolved in 7 mL of dioxane. After passing N 2 for 10 min, trimethylcyclotriboroxane (0.25 mL, 1 mmol) was added using a syringe, and the reaction mixture was sealed. The reaction was carried out at 120 ° C for 4 h. After the reaction was completed, the solid was removed by filtration, and the filtrate was evaporated to dryness, and the residue of petroleum ether: ethyl acetate = 10:1 was purified to give the title compound (0.1 g, 100% yield). MS: 198.1 (M+H+).
3-甲基 -4，5，6，7-四氢噻吩 [3，2-c]吡啶三氟乙酸盐 （化合物 113B)  3-methyl-4,5,6,7-tetrahydrothiophene [3,2-c]pyridine trifluoroacetate (compound 113B)
本品由化合物 113A按照化合物 106C的制备方法合成， 100%收率。 MS: 154.1 (M+H+). N- (2,6-二甲基 -4- ( 3-甲基 -6,7-二氢噻吩 [3，2-c]吡啶 -5 (4H) ) -苯基) 3，3-二甲基丁酰胺 (化合物 113 ) This product was synthesized from Compound 113A according to the preparation method of Compound 106C, 100% yield. MS: 154.1 (M+H + ). N-(2,6-dimethyl-4-(3-methyl-6,7-dihydrothiophene[3,2-c]pyridine-5 (4H)) -phenyl) 3,3-dimethylbutyramide (compound 113)
本品由化合物 113B按照化合物 106的制备方法合成， 14% 收率。 MS: 371.3 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 8.90 (s, 1H), 6.93 (s, 1H), 6.76 (s, 2H), 4.09 (s, 2H), 3.51 (t, J= 6.0 Hz, 2H), 2.86-2.89 (m， 2H), 2.18 (s, 2H), 2.15 (s, 3H), 2.11 (s, 6H),1.06 (s, 9H). This product was synthesized from Compound 113B according to the method for the preparation of Compound 106 in 14% yield. MS: 371.3 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 8.90 (s, 1H), 6.93 (s, 1H), 6.76 (s, 2H), 4.09 (s, 2H), 3.51 (t, J = 6.0 Hz, 2H), 2.86-2.89 (m, 2H), 2.18 (s, 2H), 2.15 (s, 3H), 2.11 (s, 6H), 1.06 (s, 9H).
实施例一百一" h四  Embodiment one hundred one" h four
N- (6- (6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基） -2,4-二甲基吡啶 -3-基） -3,3-二甲基丁酰胺 的制备
Figure imgf000098_0002
N-(6-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethyl Preparation of butylbutyramide
Figure imgf000098_0002
5- (4,6-二甲基） -5-硝基 -2-吡啶基） -4，5，6，7-四氢噻吩 [3，2-c]卩比啶 （化合物 114A) 将 4，5，6，7-四氢噻吩 [3，2-c]卩比啶 ( 1.25 g, 8.98 mmol) 溶于 20 mL 乙腈溶液中， 室温加入 5-(4,6-Dimethyl)-5-nitro-2-pyridyl)-4,5,6,7-tetrahydrothiophene [3,2-c]indolepyridinium (Compound 114A) 4 ,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (1.25 g, 8.98 mmol) dissolved in 20 mL acetonitrile solution, added at room temperature
N，N-二异丙基乙酰胺（2.32 g， 17.96 mmol)和 6-氯 -2,4-二甲基 -3-硝基吡啶（ 1.68 g， 8.98 mmol)。N,N-diisopropylacetamide (2.32 g, 17.96 mmol) and 6-chloro-2,4-dimethyl-3-nitropyridine ( 1.68 g, 8.98 mmol).
85 封管搅拌过夜， 加水， 乙酸乙酯萃取， 合并， 干燥， 经石油醚 /乙酸乙酯 =80/1过柱分离 纯化得目标产物 114A ( 1.69 g， 65% 收率） MS: 290.2 (M+H+). The mixture was stirred overnight, added with water, EtOAc EtOAc (EtOAc)EtOAc. +H + ).
5- (4,6-二甲基） -5-胺基 -2-吡啶基） -4，5，6，7-四氢噻吩 [3，2-c]卩比啶 （化合物 114B) 将化合物 114A溶于 20 mL 甲醇和 2 mL水的混合溶液中， 加入保险粉 （8.13 g， 46.72 mmol), 封管 90 °C反应过夜。 减压旋除甲醇， 加入乙酸乙酯， 滤除固体， 干燥， 旋干得化合 物 114B ( 1.50 g, 99% 收率） 。 MS: 260.2 (M+H+). N- (6- (6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基） -2，4-二甲基吡啶 -3-基） -3,3-二甲基丁酰胺 (化合物 114) 5-(4,6-Dimethyl)-5-amino-2-pyridyl)-4,5,6,7-tetrahydrothiophene[3,2-c]indolepyridinium (Compound 114B) 114A was dissolved in a mixed solution of 20 mL of methanol and 2 mL of water, and a safety powder (8.13 g, 46.72 mmol) was added, and the tube was sealed at 90 ° C overnight. Methanol was removed under reduced pressure, ethyl acetate was added and the solid was filtered, dried and evaporated to give compound 114B ( 1.50 g, 99% yield). MS: 260.2 (M+H+). N-(6-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethyl Butylamide (Compound 114)
将钠氢 （462 mg， 11.56 mmol) 悬浮于 30 mL 干燥的四氢呋喃溶液中， 加入化合物 114B ( 1.50 g， 5.78 mmo)， 搅拌 5分钟后， 降温至 0 。C , 滴加 3，3-二甲基丁酰氯 （1.56 g， 11.56 mmol)。 室温搅拌反应 4小时。 加水淬灭， 乙酸乙酯萃取， 合并， 干燥， 经石油醚 /乙酸乙酯 =8/1过柱分离纯化得目标产物 114， 用盐酸***溶液酸化得其盐酸盐， 为黄色固体 ( 1.15 g， 50%收率） 。 MS: 358.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.54 (s, 1Η)， 7.42-7.43 (d, J= 4.8 Hz, 1H)， 7.22 ( s, 1H)， 6.91-6.93 (d, J = 5.2 Hz, 1H), 4.75 (s， 2H)， 4.02-4.05 (m， 2H), 3.01 (s， 2H), 2.43 (s， 3H), 2.25 (s， 5H)， 1.05 (s， 9H).  Sodium hydrogen (462 mg, 11.56 mmol) was suspended in 30 mL of dry tetrahydrofuran, and compound 114B (1.50 g, 5.78 mmo) was added. After stirring for 5 minutes, the temperature was lowered to 0. C, 3,3-dimethylbutyryl chloride (1.56 g, 11.56 mmol) was added dropwise. The reaction was stirred at room temperature for 4 hours. After quenching with water, EtOAc, EtOAc (EtOAc)EtOAc. , 50% yield). MS: 358.2 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 9.54 (s, 1 Η), 7.42-7.43 (d, J = 4.8 Hz, 1H), 7.22 (s, 1H), 6.91 -6.93 (d, J = 5.2 Hz, 1H), 4.75 (s, 2H), 4.02-4.05 (m, 2H), 3.01 (s, 2H), 2.43 (s, 3H), 2.25 (s, 5H), 1.05 (s, 9H).
实施例一百一" h五  Example one hundred one" h five
N- (2-氯 -4- (6，7-二氢噻吩 [3，2-C]吡啶 -5 (4H) ) -6- (三氟甲基苯基） -3,3-二甲基丁酰胺 (化合物 115 )
Figure imgf000099_0001
N-(2-chloro-4-(6,7-dihydrothiophene[3,2- C ]pyridine-5(4H))-6-(trifluoromethylphenyl)-3,3-dimethyl Butyramide (compound 115)
Figure imgf000099_0001
本品由 4，5，6，7-四氢噻吩 [3，2，c]吡啶 （150 mg， 1.07 mmol) 和 N- (4-溴代 -2-氯 -6- (三氟 甲基苯基） -3.3-二甲基丁酰胺 （435 mg， 1.18 mmol) 按照化合物 115的制备方法合成， 封管 中 110°C反应 1 h，纯化得目标产物，为白色固体（30 mg， 7%收率）。 MS: 431 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.18 (d, J= 5.2 Hz, 2H), 7.13 (d, J= 2.8 Hz, 1H)， 6.87 (d, J= 5.2 Hz, 1H)， 6.37 (s, 2H), 4.38 (s, 1H)， 3.70 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 5.2 Hz, 2H), 2.31 (s, 2H), 1.16 (s, 9H). This product consists of 4,5,6,7-tetrahydrothiophene [3,2,c]pyridine (150 mg, 1.07 mmol) and N-(4-bromo-2-chloro-6-(trifluoromethylbenzene) -3.3-dimethylbutyramide (435 mg, 1.18 mmol) was synthesized according to the preparation method of compound 115, and the reaction was carried out at 110 ° C for 1 h in a sealed tube to purify the desired product as a white solid (30 mg, 7%. MS) 431 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.18 (d, J = 5.2 Hz, 2H), 7.13 (d, J = 2.8 Hz, 1H), 6.87 ( d, J = 5.2 Hz, 1H), 6.37 (s, 2H), 4.38 (s, 1H), 3.70 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 5.2 Hz, 2H), 2.31 ( s, 2H), 1.16 (s, 9H).
实施例一百一" h六  Embodiment one hundred one" h six
N- (2-氯 -4- (6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) ) -6- (甲基苯基） -3,3-二甲基丁酰胺 （化 合物 116) 的制备
Figure imgf000099_0002
N-(2-chloro-4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H))-6-(methylphenyl)-3,3-dimethylbutanamide Preparation of (Compound 116)
Figure imgf000099_0002
本品由 4，5，6，7-四氢噻吩 [3，2，c]吡啶 （150 mg， 1.07 mmol)和 N- (4-溴代 -2-氯 -6- (甲基 苯基） -3.3-二甲基丁酰胺 （375 mg， 1.18 mmol) 按照化合物 115的制备方法合成， 目标产物 为白色固体（ 120 mg， 32%收率）。 MS: 377 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.12 (s， 1Η), 7.34 (d, J= 4.8 Hz, 1H), 6.89-6.93 (m， 3H)， 4.29 (s， 2H)， 2.90 (s， 2H), 2.18 (s， 2H), 2.14 (s， 3H), 1.06 (s, 9H). This product consists of 4,5,6,7-tetrahydrothiophene [3,2,c]pyridine (150 mg, 1.07 mmol) and N-(4-bromo-2-chloro-6-(methylphenyl) -3.3-Dimethylbutanamide (375 mg, 1.18 mmol) mp mp (m.m. 400 MHz, DMSO-6) δ: 9.12 (s, 1Η), 7.34 (d, J= 4.8 Hz, 1H), 6.89-6.93 (m, 3H), 4.29 (s, 2H), 2.90 (s, 2H) , 2.18 (s, 2H), 2.14 (s, 3H), 1.06 (s, 9H).
实施例一百一" h七  Embodiment one hundred one" h seven
N- (4- ( 6,7-二氢噻吩 [3，2-C]吡啶 -5 (4H) ) -2-甲氧基 -6-甲基苯基） -3,3-二甲基丁酰胺（化 合物 117) 的制备
Figure imgf000100_0001
N-(4-(6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H))-2-methoxy-6-methylphenyl)-3,3-dimethylbutyl Preparation of amide (compound 117)
Figure imgf000100_0001
本品由 4，5，6，7-四氢噻吩 [3，2，c]吡啶 （150 mg， 1.07 mmol) 禾 B N- (4-溴代 -2-甲氧基 -6-甲 基苯基） -3.3-二甲基丁酰胺 （370 mg， 1.18 mmol) 按照化合物 115的制备方法， 110°C封管 反应 8 h， 得目标产物为白色固体（120 mg， 32%收率）。 MS: 373 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 8.66 (s, 1Η)， 7.33 (d, J= 5.2 Hz, 1H)， 6.92 (d, J= 5.2 Hz, 1H)， 6.50 (d, J= 2 Hz, 1H): 6.44 (d, J= 2.4 Hz, 1H), 4.27 (s， 2H), 3.72 (s， 3H), 3.59 (t， J= 5.2 Hz, 2H), 2.92 (t， J= 5.2 Hz, 2H), 2.12 (s， 2H), 2.08 (s， 3H), 1.05 (s， 9H). This product consists of 4,5,6,7-tetrahydrothiophene [3,2,c]pyridine (150 mg, 1.07 mmol) and B N-(4-bromo-2-methoxy-6-methylbenzene -3.3-Dimethylbutanamide (370 mg, 1.18 mmol) The title compound was obtained as a white solid (yield: 120 mg, 32% yield). MS: 373 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 8.66 (s, 1 Η), 7.33 (d, J = 5.2 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 6.50 (d, J= 2 Hz, 1H) : 6.44 (d, J= 2.4 Hz, 1H), 4.27 (s, 2H), 3.72 (s, 3H), 3.59 (t, J= 5.2 Hz, 2H), 2.92 (t, J= 5.2 Hz, 2H), 2.12 (s, 2H), 2.08 (s, 3H), 1.05 (s, 9H).
实施例一百一" h八  Embodiment one hundred one" h eight
N- (4- ( 6，7-二氢噻吩 [3，2-C]吡啶 -5 (4H) ) -2，6-二甲氧基苯基） -3,3-二甲基丁酰胺的制备
Figure imgf000100_0002
N-(4-(6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H))-2,6-dimethoxyphenyl)-3,3-dimethylbutanamide preparation
Figure imgf000100_0002
4-溴 -2,6-二甲氧基苯胺 （化合物 118A)  4-bromo-2,6-dimethoxyaniline (Compound 118A)
2，6-二乙基苯胺（2 g， 13.1 mmol)溶于50 mL二氯甲烷后，于 0 °C缓慢滴加溴素（0.8 mL， 15.7 mmol) ， 滴加完毕后， 反应液于室温搅拌 8 h， 反应液滴加水， 二氯甲烷萃取， 有机相 饱和氯化钠水洗， 有机相减压旋干， 石油醚： 乙酸乙酯 =5: 1分离纯化得目标化合物 （2.7 g， 90%收率） 。 MS: 232 (M+H+).  After dissolving 2,6-diethylaniline (2 g, 13.1 mmol) in 50 mL of dichloromethane, slowly add bromine (0.8 mL, 15.7 mmol) at 0 °C. After the addition, the reaction solution was at room temperature. After stirring for 8 h, the reaction liquid was added with water, extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride, and the organic phase was evaporated to dryness. The petroleum ether: ethyl acetate = 5: 1 was purified to obtain the target compound (2.7 g, 90%) Yield). MS: 232 (M+H+).
N- (4-溴 -2,6-二甲氧基苯胺） -3,3-二甲基丁酰胺 （化合物 118B )  N-(4-bromo-2,6-dimethoxyaniline)-3,3-dimethylbutanamide (Compound 118B)
化合物 118A (2.7 g, 12.3 mmol) 与三乙胺 （4.7 mL， 36.8 mmol) 溶于 50 mL二氯甲烷 中， 于 0 °C滴加 3，3-二甲基丁酰氯 （2.04 mL， 14.7 mmol) 的 10 mL二氯甲烷溶液， 反应液 室温搅拌 2 h，水洗， 乙酸乙酯萃取，石油醚： 乙酸乙酯 =5: 1分离纯化得目标化合物为固体（3 g， 74%收率） 。 MS: 330 (M+H+).  Compound 118A (2.7 g, 12.3 mmol) and triethylamine (4.7 mL, 36.8 mmol) were dissolved in 50 mL dichloromethane. &lt;RTI ID=0.0&gt;&gt; A solution of 10 mL of dichloromethane was stirred at room temperature for 2 h, washed with EtOAc EtOAc (EtOAc) MS: 330 (M+H+).
N- (4- ( 6,7-二氢噻吩 [3，2-c]吡啶 -5 (4H) ) -2,6-二甲氧基苯基） -3,3-二甲基丁酰胺 （化合 物 118 )  N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H))-2,6-dimethoxyphenyl)-3,3-dimethylbutanamide Compound 118)
本品由 4，5，6，7-四氢噻吩 [3，2，c]吡啶和化合物 118B ( 389 mg， 1.18 mmol)按照化合物 115 的制备方法合成， 目标产物为白色固体（200 mg， 50%收率）。 MS: 389 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.40 (s, 1H), 7.34 (d, J= 5.2 Hz, 1H), 6.93 (d, J= 5.2 Hz, 1H), 6.28 (s，2H)， 4.31 (s， 2H), 3.71 (s， 6H)， 3.62 (t, J= 5.2 Hz, 2H), 2.93-2.95 (m， 2H), 2.08 (s， 2H), 1.03 (s， 9H). 实施例一百一" h九 This product consists of 4,5,6,7-tetrahydrothiophene [3,2,c]pyridine and compound 118B (389 mg, 1.18 mmol) according to compound 115 The preparation was carried out as a white solid (200 mg, 50% yield). MS: 389 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.40 (s, 1H), 7.34 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 6.28 (s, 2H), 4.31 (s, 2H), 3.71 (s, 6H), 3.62 (t, J = 5.2 Hz, 2H), 2.93-2.95 (m, 2H), 2.08 (s, 2H) ), 1.03 (s, 9H). Example one hundred one "h nine
N- ( 的制备
Figure imgf000101_0001
Preparation of N-
Figure imgf000101_0001
4-溴 -2,6-二乙基苯胺 （化合物 119A)  4-bromo-2,6-diethylaniline (Compound 119A)
2，6-二乙基苯胺（2 g， 13.3 mmol)溶于 50 mL二氯甲烷后， 于 0 °C缓慢滴加溴素 （0.83 mL， 16 mmol) ， 滴加完毕后， 反应液于室温搅拌 8 h， 反应液滴加水， 二氯甲烷萃取， 有机 相饱和氯化钠水洗， 有机相减压旋干， 石油醚： 乙酸乙酯 =5:1分离纯化得目标化合物 （3 g， 99%收率） 。 MS: 228 (M+H+).  After dissolving 2,6-diethylaniline (2 g, 13.3 mmol) in 50 mL of dichloromethane, slowly add bromine (0.83 mL, 16 mmol) at 0 °C. After the addition, the reaction solution was at room temperature. After stirring for 8 h, the reaction liquid was added with water, extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride, and the organic phase was evaporated to dryness. The petroleum ether: ethyl acetate = 5:1 was isolated and purified to obtain the target compound (3 g, 99%) Yield). MS: 228 (M+H+).
N- (4-溴 -2,6-二乙基苯胺） -3,3-二甲基丁酰胺 （化合物 119B)  N-(4-bromo-2,6-diethylaniline)-3,3-dimethylbutanamide (compound 119B)
化合物 119A (3 g, 13.2 mmol)与三乙胺（5.1 mL， 39.5 mmol)溶于 50 mL二氯甲烷中， 于 0 °C滴加 3，3-二甲基丁酰氯（2.2 mL， 15.8 mmol) 的 10 mL二氯甲烷溶液， 反应液室温搅 拌 2 h， 水洗， 乙酸乙酯萃取， 石油醚： 乙酸乙酯 =5:1分离纯化得目标化合物为固体 （3.5 g， 81%收率） 。 MS: 326 (M+H+).  Compound 119A (3 g, 13.2 mmol) and triethylamine (5.1 mL, 39.5 mmol) were dissolved in 50 mL dichloromethane, and then, 3,3-dimethylbutyryl chloride (2.2 mL, 15.8 mmol) A solution of 10 mL of dichloromethane was stirred at room temperature for 2 h, washed with EtOAc EtOAc (EtOAc) MS: 326 (M+H+).
N- (4- (6,7-二氢噻吩 [3，2-c]吡啶 -5 (4H)) -2,6-二乙基苯基） -3,3-二甲基丁酰胺 （化合物 N-(4-(6,7-Dihydrothiophene [3,2-c]pyridine -5 (4H)) -2,6-diethylphenyl) -3,3-dimethylbutanamide (compound
119) 119)
本品由 4，5，6，7-四氢噻吩 [3，2，c]吡啶 （150 mg， 1.07 mmol)和化合物 119B (385 mg， 1.18 mmol)按照化合物 115的制备方法合成， 目标产物为白色固体（200 mg， 49%收率）。 MS: 385 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.86 (s, 1Η)， 7.33 (d, J= 5.2 Hz, 1H)， 6.93 (d, J= 5.2 Hz, 1H), 6.72 (s, 2H)， 4.26 (s， 2H), 3.57 (t，J= 7 Hz, 2H), 2.92 (t，J= 7 Hz, 2H), 2.42-2.50 (m， 4H)， 2.19 (s， 2H), 1.06-1.10 (m， 15H).  This product was synthesized from 4,5,6,7-tetrahydrothiophene [3,2,c]pyridine (150 mg, 1.07 mmol) and compound 119B (385 mg, 1.18 mmol) according to the preparation of compound 115. White solid (200 mg, 49% yield). MS: 385 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 8.86 (s, 1 Η), 7.33 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H ), 6.72 (s, 2H), 4.26 (s, 2H), 3.57 (t, J = 7 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 2.42-2.50 (m, 4H), 2.19 (s, 2H), 1.06-1.10 (m, 15H).
实施例一百二十  Example one hundred twenty
N-(4-(6，7-二氢噻吩 [3，2-C]哌啶 -5(4H)-基) -2- (甲基)苯基 -3，3-二甲基丁酰胺的制备
Figure imgf000101_0002
N-(4-(6,7-Dihydrothiophene[3,2- C ]piperidin-5(4H)-yl)-2-(methyl)phenyl-3,3-dimethylbutanamide preparation
Figure imgf000101_0002
N-(4-溴 -2-甲苯基 )-3，3-二甲基丁酰胺 （化合物 120A) 0 °C下向 4-溴 -2-甲基苯胺 (3.7g， 20.0mmol)和三乙胺 (6.0mL，40.0mmol)的二氯甲烷溶液中 缓慢滴加叔丁基乙酰氯 (3.0ml，21.8mmol)的二氯甲烷溶液， 滴毕逐渐升至室温反应 12h， 反应 结束加入饱和氯化铵萃灭反应， 分液， 有机层用无水硫酸钠干燥， 减压浓縮， 柱层析 （石油 醚 /乙酸乙酯 =5/1 ) 得化合物 120A (4.2g， 78%产率）。 N- (4-bromo-2-methylphenyl)-3,3-dimethylbutanamide (compound 120A) To a solution of 4-bromo-2-methylaniline (3.7 g, 20.0 mmol) and triethylamine (6.0 mL, 40.0 mmol) in dichloromethane, m. 21.8 mmol) of a dichloromethane solution, the mixture was gradually warmed to room temperature for 12 h, and the reaction mixture was added to a saturated aqueous solution of ammonium chloride, and the organic layer was dried over anhydrous sodium sulfate. Petroleum ether / ethyl acetate = 5 / 1) Compound 120A (4.2 g, 78% yield).
N-(4-(6，7-二氢噻吩 [3，2-c]哌啶 -5(4H)-基) -2- (甲基)苯基) -3,3-二甲基丁酰胺 （化合物 120) 化合物 120A(283 mg， 1.0 mmol), 4，5，6，7-四氢噻吩 [3，2-c]哌啶 (141 mg， 1.2 mmol),三（二 苄基丙酮）二钯 （0) (55 mg， 0.05 mmol), X-phos (24 mg, 0.05mmol) 及叔丁醇钾 （336 mg， 3 mmol) 加入到甲苯 （15 ml) 中。 在 N2保护下， 升温至 100°C 反应 12小时， 反应结束减压 旋干溶剂， 柱层析纯化得目标产物， MS: 365 (M+H+)。 iHNMR (DMSO, 400 MHz): δ 7.56 (d， J=8.4Hz，lH)， 7.14 (d, J=4.0 Ηζ,ΙΗ), 6.85 (d, J=4.0 Hz,3H), 6.78 (s， 1H)， 4.29 (s， 2H),3.59 (s， 2H), 2.99(s, 2H), 2.26 (s， 5H)， 1.14 (s， 9H). N-(4-(6,7-Dihydrothiophene[3,2-c]piperidin-5(4H)-yl)-2-(methyl)phenyl)-3,3-dimethylbutanamide (Compound 120) Compound 120A (283 mg, 1.0 mmol), 4,5,6,7-tetrahydrothiophene [3,2-c]piperidine (141 mg, 1.2 mmol), tris(dibenzylacetone) Palladium (0) (55 mg, 0.05 mmol), X-phos (24 mg, 0.05 mmol) and potassium t-butoxide (336 mg, 3 mmol) were added to toluene (15 ml). The mixture was heated to 100 ° C for 12 hours under N 2 protection. After the reaction was completed, the solvent was evaporated to dryness, and purified to purified to afford the desired product, MS: 365 (M+H + ). iHNMR (DMSO, 400 MHz): δ 7.56 (d, J = 8.4 Hz, lH), 7.14 (d, J = 4.0 Ηζ, ΙΗ), 6.85 (d, J = 4.0 Hz, 3H), 6.78 (s, 1H) ), 4.29 (s, 2H), 3.59 (s, 2H), 2.99(s, 2H), 2.26 (s, 5H), 1.14 (s, 9H).
实施例一百二 ^一  Example one hundred two ^ one
N-(4-(6，7-二 噻吩 [3，2-C]哌啶 -5(4H)-基) -2- (氯)苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000102_0001
Preparation of N-(4-(6,7-dithiophene[3,2- C ]piperidin-5(4H)-yl)-2-(chloro)phenyl)-3,3-dimethylbutanamide
Figure imgf000102_0001
N-(4-溴 -2-氯苯基 )-3，3-二甲基丁酰胺 （化合物 121A) N- (4-bromo-2-chlorophenyl)-3,3-dimethylbutanamide (Compound 121A)
0 °C下向 4-溴 -2-氯苯胺 (4.1 g， 20.0mmol)和三乙胺 (6.0mL，40.0mmol)的二氯甲烷溶液中缓 慢滴加叔丁基乙酰氯 (3.0ml，21.8mmol)的二氯甲烷溶液， 滴毕逐渐升至室温反应 12h， 反应结 束加入饱和氯化铵萃灭反应， 分液， 有机层用无水硫酸钠干燥， 减压浓縮， 柱层析 （石油醚 / 乙酸乙酯 =5/1 ) 得化合物 121A (4.2g， 78%产率）。  To a solution of 4-bromo-2-chloroaniline (4.1 g, 20.0 mmol) and triethylamine (6.0 mL, 40.0 mmol) in dichloromethane was slowly added dropwise t-butylacetyl chloride (3.0 ml, 21.8) Methylene chloride solution was added dropwise to room temperature for 12 h. At the end of the reaction, saturated ammonium chloride was added and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. Ether / ethyl acetate = 5 / 1) Compound 121A (4.2 g, 78% yield).
N-(4-(6，7-二氢噻吩 [3，2-C]哌啶 -5(4H)-基) -2- (氯)苯基) -3,3-二甲基丁酰胺 （化合物 121 ) 本品由化合物 121A(303 mg, 1.0 mmol)和 4，5，6，7-四氢噻吩 [3，2-c]哌啶 (141 mg, 1.2 mmol) 按照化合物 120的制备方法合成，得目标产物 （273 mg, 80% yield), MS: 365 (M+H+). 1HNMR (DMSO, 400 MHz): δ 8.18 (d， J=8.4Hz,lH), 7.14 (d， J=4.0 Ηζ,ΙΗ), 6.85 (d， J=4.0 Hz，2H)， 6.78 (s， 1H), 4.29 (s, 2H),3.59 (s, 2H), 2.99(s, 2H), 2.26 (s, 2H), 1.14 (s, 9H) N-(4-(6,7-Dihydrothiophene[3,2- C ]piperidin-5(4H)-yl)-2-(chloro)phenyl)-3,3-dimethylbutanamide Compound 121) This product was synthesized from compound 121A (303 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]piperidine (141 mg, 1.2 mmol) according to the preparation of compound 120. The desired product (273 mg, 80% yield), MS: 365 (M+H + ). 1HNMR (DMSO, 400 MHz): δ 8.18 (d, J = 8.4 Hz, lH), 7.14 (d, J = 4.0 Ηζ,ΙΗ), 6.85 (d, J=4.0 Hz, 2H), 6.78 (s, 1H), 4.29 (s, 2H), 3.59 (s, 2H), 2.99(s, 2H), 2.26 (s, 2H), 1.14 (s, 9H)
实施例一百二十二  Example one hundred twenty two
Ν-(4-(6，7-二 [3，2-C]哌啶 -5(4H)-基) -2- (三氟甲基)苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000102_0002
N-(4-溴 -2- (三氟甲基)苯基) -3，3-二甲基丁酰胺 （化合物 122A) Ν-(4-(6,7-bis[3,2- C ]piperidin-5(4H)-yl)-2-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide Preparation
Figure imgf000102_0002
N-(4-bromo-2-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (Compound 122A)
0 °C下向 4-溴 -2-氯苯胺 (4.8g， 20.0mmol)和三乙胺 (6.0mL，40.0mmol)的二氯甲烷溶液中缓 慢滴加叔丁基乙酰氯 (3.0ml，21.8mmol)的二氯甲烷溶液， 滴毕逐渐升至室温反应 12h， 反应结 束加入饱和氯化铵萃灭反应， 分液， 有机层用无水硫酸钠干燥， 减压浓縮， 柱层析 （石油醚 / 乙酸乙酯 =5/1 ) 得化合物 122A (4.2g， 78%产率）。  To a solution of 4-bromo-2-chloroaniline (4.8 g, 20.0 mmol) and triethylamine (6.0 mL, 40.0 mmol) in dichloromethane was slowly added dropwise t-butylacetyl chloride (3.0 ml, 21.8). Methylene chloride solution was added dropwise to room temperature for 12 h. At the end of the reaction, saturated ammonium chloride was added and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. Ether / ethyl acetate = 5 / 1) Compound 122A (4.2 g, 78% yield).
N-(4-(6，7-二氢噻吩 [3，2-C]哌啶 -5(4H)-基) -2- (三氟甲基)苯基) -3,3-二甲基丁酰胺 （化合物 122B) N-(4-(6,7-Dihydrothiophene[3,2- C ]piperidin-5(4H)-yl)-2-(trifluoromethyl)phenyl)-3,3-dimethyl Butyramide (Compound 122B)
本品由化合物 122A(337 mg， 1.0 mmol)和 4，5，6，7-四氢噻吩 [3，2-c]哌啶 （141 mg， 1.2 mmol) 按照化合物 120的制备方法合成，得目标产物 （273 mg， 80%收率)， MS: 365 (M+H+)。 i iNMR (DMSO, 400 MHz): δ 8.18 (d, J=8.4Hz，lH)， 7.17 (m，4H)， 6.85 (d， J=4.0 Ηζ,ΙΗ), 4.29 (s, 2H),3.59 (s， 2H), 2.99(s, 2H), 2.26 (s， 2H), 1.14 (s， 9H). This product is synthesized from compound 122A (337 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]piperidine (141 mg, 1.2 mmol) according to the preparation method of compound 120. Product (273 mg, 80% yield), MS: 365 (M+H + ). i iNMR (DMSO, 400 MHz): δ 8.18 (d, J = 8.4 Hz, lH), 7.17 (m, 4H), 6.85 (d, J = 4.0 Ηζ, ΙΗ), 4.29 (s, 2H), 3.59 ( s, 2H), 2.99(s, 2H), 2.26 (s, 2H), 1.14 (s, 9H).
实施例一百二十三  Example one hundred twenty three
3-环戊基 -N- (4 (6,7-二氢噻吩 [3， 2-c]哌啶 -5 (4H) -2,6 二甲基苯基） 丙酰胺 （化合物 123 ) 的制备
Figure imgf000103_0001
Preparation of 3-cyclopentyl-N-(4 (6,7-dihydrothiophene[3,2-c]piperidin-5(4H)-2,6-dimethylphenyl)propanamide (Compound 123)
Figure imgf000103_0001
本品由 N- (4-溴 -2,6-二甲基苯基） -3-环戊基丙酰胺 (323mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]哌啶 （141 mg， 1.2 mmol)按照化合物 120的制备方法合成， 得目标产物 （229 mg， 50% 收率）， MS: 365 (M+H+)。 iHNMR (DMSO, 400 MHz): δ 7.15 (m， 1H), 6.86 (m， 1H), 6.72 (m， 2H), 6.60 (s，lH)， 4.30 (m， 2H),3.67 (s， 2H), 2.99(s, 2H), 2.42 (m， 2H), 2.15 (s， 6H)， 1.8-1. l(m， 11H). 实施例一百二十四  This product consists of N-(4-bromo-2,6-dimethylphenyl)-3-cyclopentylpropanamide (323 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3, 2-c]piperidine (141 mg, 1.2 mmol) was synthesized according to the procedure of Compound 120 to give the desired product (229 mg, 50% yield), MS: 365 (M+H+). iHNMR (DMSO, 400 MHz): δ 7.15 (m, 1H), 6.86 (m, 1H), 6.72 (m, 2H), 6.60 (s,lH), 4.30 (m, 2H), 3.67 (s, 2H) , 2.99(s, 2H), 2.42 (m, 2H), 2.15 (s, 6H), 1.8-1. l(m, 11H). Example one hundred twenty four
3-环己基 -N- (4 (6,7-二氢噻吩 [3， 2-c]哌啶 -5 (4H) -2,6 二甲基苯基） 丙酰胺 （化合物 124) 的制备
Figure imgf000103_0002
Preparation of 3-cyclohexyl-N-(4 (6,7-dihydrothiophene[3,2-c]piperidin-5(4H)-2,6-dimethylphenyl)propanamide (Compound 124)
Figure imgf000103_0002
本品由 N- (4-溴 -2,6-二甲基苯基） -3-环己基丙酰胺 (338mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]哌啶 （141 mg， 1.2 mmol) 按照化合物 120的制备方法合成， 得目标产物 （195 mg， 50% 收率）， MS: 365 (M+H+)。 iHNMR (DMSO, 400 MHz): δ 7.15 (m， 1H), 6.86 (m， 1H), 6.72 (m， 2H), 6.60 (s，lH)， 4.30 (m， 2H),3.67 (s, 2H), 2.99(s, 2H), 2.42 (m， 2H), 2.15 (s, 6H)， 1.8-1. l(m， 13H). 实施例一百二十五 This product consists of N-(4-bromo-2,6-dimethylphenyl)-3-cyclohexylpropanamide (338 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2 -c] piperidine (141 mg, 1.2 mmol) was synthesized according to the procedure of compound 120 to give the desired product (195 mg, 50% yield), MS: 365 (M+H+). iHNMR (DMSO, 400 MHz): δ 7.15 (m, 1H), 6.86 (m, 1H), 6.72 (m, 2H), 6.60 (s,lH), 4.30 (m, 2H), 3.67 (s, 2H) , 2.99(s, 2H), 2.42 (m, 2H), 2.15 (s, 6H), 1.8-1. l(m, 13H). Example one hundred twenty five
2- ( Or, 5r， 7r) -金刚烷 -1-基) -N- (4- (6， 7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲 基苯)乙酰胺 （化合物 125 ) 的制备
Figure imgf000104_0001
2-( Or, 5r, 7r)-adamantan-1-yl)-N-(4-(6, 7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2, Preparation of 6-dimethylphenyl)acetamide (Compound 125)
Figure imgf000104_0001
本品由 2- ( Or, 5r， 7r) -金刚烷 -1-基) -N- (4善 2， 6-二甲基苯) 乙酰胺 (594 mg,1.58 mmol) 和 4，5，6，7-四氢噻吩 [3，2-c]吡啶 (200mg，0.44 mmol) 按照化合物 120的制备方法合成，氮 气保护下 110°C反应 12小时得到化合物 125(120 mg，20%收率）。 MS: 435.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.85 (s， 1H), 7.32(t, J = 5.2 Hz, 2H), 6.91 (d， J = 5.2 Hz, 1H)， 6.72 (s， 2H), 4.23 (s, 2H), 3.55 (m， 2H), 2.90(m, 2H), 2.10 (m， 12H), 1.67 (m， 11H). This product consists of 2-( Or, 5r, 7r)-adamantan-1-yl)-N- (4 good 2, 6-dimethylphenyl) acetamide (594 mg, 1.58 mmol) and 4,5,6 , 7-Tetrahydrothiophene [3,2-c]pyridine (200 mg, 0.44 mmol) was synthesized according to the preparation method of Compound 120, and reacted at 110 ° C for 12 hours under nitrogen atmosphere to give Compound 125 (120 mg, 20% yield). MS: 435.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.85 (s, 1H), 7.32 (t, J = 5.2 Hz, 2H), 6.91 (d, J = 5.2 Hz, 1H), 6.72 (s, 2H), 4.23 (s, 2H), 3.55 (m, 2H), 2.90 (m, 2H), 2.10 (m, 12H), 1.67 (m, 11H).
实施例一百二十六  Example one hundred and twenty six
2-环戊基 -N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯)乙酰胺（化合物 126)的 制备
Figure imgf000104_0002
2-cyclopentyl-N-(4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)acetamide (Compound 126 Preparation
Figure imgf000104_0002
本品由 N- (4-溴 -2， 6-二甲基） -2-环戊乙酰胺 （488 mg，1.58 mmol) 和 4，5，6，7-四氢噻吩  This product consists of N-(4-bromo-2,6-dimethyl)-2-cyclopentylacetamide (488 mg, 1.58 mmol) and 4,5,6,7-tetrahydrothiophene
[3，2-c]吡啶三氟乙酸盐 (200mg，0.79 mmol) 按照化合物 120的制备方法合成，氮气保护下 110°C 反应 12小时得到化合物 126(100 mg，20%收率）。 MS: 369.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.94 (s, 1H)， 7.33 (d, J= 5.2 Hz, 2H), 6.91 (d, J= 5.2 Hz, 1H)， 6.72 (s, 2H), 4.24 (s, 2H), 3.56 (m， 2H), 2.88 (m， 2H), 2.26 (m， 2H), 2.08 (s， 6H)， 1.76 (m， 2H), 1.52 (m， 4H)， 1.23 (m， 3H). [3,2-c]pyridine trifluoroacetate (200 mg, 0.79 mmol) was synthesized according to the preparation of compound 120, and reacted at 110 ° C for 12 hours under nitrogen to give compound 126 (100 mg, 20% yield). MS: 369.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.94 (s, 1H), 7.33 (d, J = 5.2 Hz, 2H), 6.91 (d, J = 5.2 Hz, 1H), 6.72 (s, 2H), 4.24 (s, 2H), 3.56 (m, 2H), 2.88 (m, 2H), 2.26 (m, 2H), 2.08 (s, 6H), 1.76 (m, 2H) ), 1.52 (m, 4H), 1.23 (m, 3H).
实施例一百二十七  Example one hundred twenty seven
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 4H)-基) -2，6-二甲基苯) -4-甲戊酰胺（化合物 127)的制备
Figure imgf000104_0003
Preparation of N-(4-(6,7-dihydrothiophene[3,2-c]pyridine-5 4H)-yl)-2,6-dimethylphenyl)-4-methylpentanamide (Compound 127)
Figure imgf000104_0003
本品由 N- (4-溴 -2， 6-二甲基） -4-甲基戊酰胺 （469 mg， 1.58 mmol)和 4，5，6，7-四氢噻吩  This product consists of N-(4-bromo-2,6-dimethyl)-4-methylpentanamide (469 mg, 1.58 mmol) and 4,5,6,7-tetrahydrothiophene
[3，2-c]吡啶 C200mg，0.44 mmol) 按照化合物 120的制备方法合成，氮气保护下 110°C反应 12小 时得到产物 （100 mg，19%收率）。 MS: 357.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.97 (s， 1H), 7.33 (d, J= 4.8 Hz, 2H), 6.91 (d, J= 4.8 Hz, 1H), 6.74 (s, 2H), 4.25 (s, 2H), 3.56 (m， 2H), 2.90 (m， 2H), 2.28 (m， 2H), 2.08 (s, 6H)， 1.53 (m， 3H), 0.90 (d， J= 6.8 Hz, 6H). [3,2-c]pyridine C 200 mg, 0.44 mmol) was synthesized according to the preparation of compound 120, and was reacted for 12 hours at 110 ° C under nitrogen atmosphere to afford product (100 mg, 19% yield). MS: 357.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.97 (s, 1H), 7.33 (d, J= 4.8 Hz, 2H), 6.91 (d, J= 4.8 Hz, 1H), 6.74 (s, 2H), 4.25 (s, 2H), 3.56 (m, 2H), 2.90 ( m, 2H), 2.28 (m, 2H), 2.08 (s, 6H), 1.53 (m, 3H), 0.90 (d, J = 6.8 Hz, 6H).
实施例一百二十八  Example one hundred twenty eight
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 4H)-基) -2，6-二甲基苯) -3-甲丁酰胺（化合物 128)的制备
Figure imgf000105_0001
Preparation of N-(4-(6,7-dihydrothiophene[3,2-c]pyridine-5 4H)-yl)-2,6-dimethylphenyl)-3-carboxamide (Compound 128)
Figure imgf000105_0001
本品由 N- (4-溴 -2， 6-二甲基) -3-甲基丁酰胺 (247 mg,0.87 mmol) 和 4，5，6，7-四氢噻吩 [3，2-c]吡啶三氟乙酸盐 (200mg，0.79 mmol) 按照化合物 120的制备方法合成，氮气保护下 110°C 反应 12 小时得到化合物 128(120 mg，33%收率）。 MS: 343.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.94 (s, 1H), 7.32 (d, J= 4.8 Hz, 2H), 6.91 (d, J= 4.8 Hz, 1H), 6.72 (s, 2H), 4.24 (s, 2H), 3.56 (m， 2H), 2.90 (m， 2H), 2.15 (m， 9H)， 0.96 (m， 6H). This product consists of N-(4-bromo-2,6-dimethyl)-3-methylbutanamide (247 mg, 0.87 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c Pyridine trifluoroacetate (200 mg, 0.79 mmol) was synthesized according to the procedure for the preparation of compound 120, and reacted for 12 hours at 110 ° C under nitrogen to give compound 128 (120 mg, 33% yield). MS: 343.2 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.94 (s, 1H), 7.32 (d, J = 4.8 Hz, 2H), 6.91 (d, J = 4.8 Hz, 1H), 6.72 (s, 2H), 4.24 (s, 2H), 3.56 (m, 2H), 2.90 (m, 2H), 2.15 (m, 9H), 0.96 (m, 6H).
实施例一百二十九  Example one hundred twenty nine
N-(4-(6，7-二氢噻吩 3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯) -3-甲戊酰胺（化合物 129)的制备
Figure imgf000105_0002
Preparation of N-(4-(6,7-dihydrothiophene 3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3-methylpentanamide (Compound 129)
Figure imgf000105_0002
本品由 N- (4-溴 -2， 6-二甲基) -3-甲基戊酰胺 (247 mg,0.87 mmol) 和 4，5，6，7-四氢噻吩 [3，2-c]吡啶三氟乙酸盐 (200mg，0.79 mmol) 按照化合物 120的制备方法合成，氮气保护下 110°C 反应 12 小时得到化合物 129(120 mg，32%收率）。 MS: 357.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.95 (s, 1H), 7.32 (d, J= 4.8 Hz, 1H), 6.91 (d, J= 4.8 Hz, 1H), 6.72 (s, 2H), 4.23 (s, 2H), 3.56 (m， 2H), 2.91 (m， 2H), 2.27 (m， 1H), 2.13 (s， 7H), 1.87 (m， 1H), 1.39 (m， 1H), 1.22 (m， 1H), 0.89 (m， 6H). This product consists of N-(4-bromo-2,6-dimethyl)-3-methylpentanamide (247 mg, 0.87 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c Pyridine trifluoroacetate (200 mg, 0.79 mmol) was synthesized according to the procedure for the preparation of compound 120. The reaction was carried out at 110 ° C for 12 hours under nitrogen to afford compound 129 (120 mg, 32% yield). MS: 357.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.95 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 6.72 (s, 2H), 4.23 (s, 2H), 3.56 (m, 2H), 2.91 (m, 2H), 2.27 (m, 1H), 2.13 (s, 7H), 1.87 (m, 1H) ), 1.39 (m, 1H), 1.22 (m, 1H), 0.89 (m, 6H).
实施例一百三十  Example one hundred thirty
N-C4-C6，7-二氢噻 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯 3-苯丙酰胺（化合物 130)的制备
Figure imgf000105_0003
Preparation of N-C4-C6,7-dihydrothia[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylbenzene 3-phenylpropanamide (Compound 130)
Figure imgf000105_0003
本品由 N- (4-溴 -2， 6-二甲基苯) 3-苯基丙酰胺 (300 mg, 0.87 mmol) 和 4，5，6，7-四氢噻 吩 [3，2-c]吡啶三氟乙酸盐 (200mg，0.79 mmol) 按照化合物 120 的制备方法合成， 氮气保护下 110°C反应 5小时得到化合物 130 (120 mg，30%收率）。 MS: 405.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.95 (s, 1H), 7.31 (m， 4H)， 7.21 (m， 1H), 6.90 (d, J = 1.2 Hz, 1H), 6.67 (s, 2H), 4.21 (s， 2H), 3.53 (m， 2H), 3.26 (m， 1H), 2.88 (m， 2H), 2.58 (m， 2H), 1.26 (m， 3H). This product consists of N-(4-bromo-2,6-dimethylphenyl) 3-phenylpropanamide (300 mg, 0.87 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c Pyridine trifluoroacetate (200 mg, 0.79 mmol) was synthesized according to the preparation of compound 120, and reacted at 110 ° C for 5 hours under nitrogen to give compound 130 (120 mg, 30% yield). MS: 405.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.95 (s, 1H), 7.31 (m, 4H), 7.21 (m, 1H), 6.90 (d, J = 1.2 Hz, 1H), 6.67 (s, 2H), 4.21 (s, 2H), 3.53 (m, 2H), 3.26 (m, 1H), 2.88 (m, 2H), 2.58 (m, 2H), 1.26 (m, 3H).
实施例一百三 ^一  Embodiment one hundred and three ^ one
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基) -3- (呋喃 -2-基)丙酰胺 （化合物 131 ) 的制备
Figure imgf000106_0001
N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3-(furan-2-yl) Preparation of propionamide (compound 131)
Figure imgf000106_0001
本品由 4，5，6，7-四氢噻吩 [3，2-c]卩比啶 (40 mg， 0.28 mmol)和 N-(4-溴 -2,6-二甲基苯基)- -3- (呋 喃 -2-基)丙酰胺 （90 mg， 0.28 mmol)按照化合物 120的制备方法合成，得到目标产物 （54mg， 收 率 50 %)。 MS: 381.3 (M+H+). 1H NMR (400 MHz, DMSO) S: 9.05 (s，lH)， 7.53 ( s， 1H)， 7.32 This product consists of 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (40 mg, 0.28 mmol) and N-(4-bromo-2,6-dimethylphenyl)- -3-(Furan-2-yl)propanamide (90 mg, 0.28 mmol) was obtained according to the procedure of Compound 120 to give the desired product (54mg, yield 50%). MS: 381.3 (M+H+). 1H NMR (400 MHz, DMSO) S: 9.05 (s,lH), 7.53 (s, 1H), 7.32
( d，J=5.2 Hz， 1H)， 6.91 ( d， J=5.2 Hz, 1H)， 6.70 (s, 2H), 6.37 (dd, J=2 Hz, 1H), 6.15 (dd, J=2 Hz, 1H)， 4.23 (s， 2H), 3.55 (t， J=5.6 Hz 2H)， 2.91 (m， 4H)， 2.62 (t， J=5.2 Hz, 2H), 2.04 (s， 6H). 实施例一百三十二 (d, J=5.2 Hz, 1H), 6.91 (d, J=5.2 Hz, 1H), 6.70 (s, 2H), 6.37 (dd, J=2 Hz, 1H), 6.15 (dd, J=2 Hz , 1H), 4.23 (s, 2H), 3.55 (t, J = 5.6 Hz 2H), 2.91 (m, 4H), 2.62 (t, J = 5.2 Hz, 2H), 2.04 (s, 6H). One hundred thirty two
N-(4- 6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基) -2-苯乙酰胺的制备
Figure imgf000106_0002
Preparation of N-(4- 6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-phenylacetamide
Figure imgf000106_0002
苯乙酰氯 （化合物 132A)  Phenylacetyl chloride (Compound 132A)
将苯乙酸 (882 mg， 6.49 mmol)溶于二氯甲烷 （20 mL) 加入草酰氯 (2.74 mL， 32.44 mmol) 和 （0.2 mL), 该反应液在室温下搅拌 3小时。 旋干后粗产品直接用于下一步反应 （ 1 g， 90% 收率）  Phenylacetic acid (882 mg, 6.49 mmol) was dissolved in dichloromethane (20 mL). oxalyl chloride (2.74 mL, 32.44 mmol) and (0.2 mL), and the mixture was stirred at room temperature for 3 hours. After spinning, the crude product is directly used in the next reaction (1 g, 90% yield)
N-(4-溴 -2,6-二甲基苯基) -2-苯基乙酰胺 （化合物 132B) N- (4-bromo-2,6-dimethylphenyl)-2-phenylacetamide (compound 132B)
在室温下，将 4-溴 -2,6-二甲基苯胺 （1.4 g， 7.0 mmol) 和三乙胺 (1.2 mL， 8.72 mmol)在二氯 甲烷 (50 mL)中搅拌半个小时，然后将苯乙酰氯 （899 g， 5.83 mmol) 逐滴的加入到上述溶液中， 室温下搅拌过夜。 用水 （lOO mL)淬灭， 分离有机相， 有机相用饱和的食盐水洗涤， 无水硫酸 钠干燥， 旋干， 粗产品用 (二氯甲烷和石油醚)重结晶得到目标产物 (1.50 g， 收率 81%)。  4-Bromo-2,6-dimethylaniline (1.4 g, 7.0 mmol) and triethylamine (1.2 mL, 8.72 mmol) were stirred in dichloromethane (50 mL) for half an hour at room temperature then Phenylacetyl chloride (899 g, 5.83 mmol) was added dropwise to the above solution and stirred at room temperature overnight. After quenching with water (100 mL), EtOAc (EtOAc m. Yield 81%).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -2-苯乙酰胺 （化合物 132) 本品由 4，5，6，7-四氢噻吩 [3，2-c]吡啶 （70 mg， 0.5 mmol)和 N-(4-溴 -2,6-二甲基苯基) -2-苯 乙酰胺 （159 mg， 0.5 mmol)按照化合物 120的制备方法合成， 纯化得到目标产物 （100 mg， 收 率 50 %)。 MS: 377.3 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.22 (s， 1Η), 7.40 (m， 6H)， 6.91 (d, J=5.2 Hz, 1H)， 6.70 (s， 1H), 4.23 (s， 2H), 3.60 (s， 2H)， 3.55 (t，J= 5.6 Hz, 2H), 2.51 (t, J=5.2 Hz, 2H), 2.03 (s, 6H). N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-phenylacetamide (Compound 132) This product consists of 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (70 mg, 0.5 mmol) and N-(4-bromo-2,6-dimethylphenyl)-2- Phenylacetamide (159 mg, 0.5 mmol) was synthesized according to the procedure for the preparation of compound 120, which was purified to give the desired product (100 mg, yield 50%). MS: 377.3 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.22 (s, 1 Η), 7.40 (m, 6H), 6.91 (d, J=5.2 Hz, 1H), 6.70 (s, 1H), 4.23 (s, 2H), 3.60 (s, 2H), 3.55 (t, J= 5.6 Hz, 2H), 2.51 (t, J= 5.2 Hz, 2H), 2.03 (s, 6H).
实施例一百三十三  Example one hundred thirty three
N-(4-(6， -二氢噻吩 [3，2-C]吡啶 -5(4H)-基) -2，6-二甲基苯基) -2-(3-氟苯基乙酰胺的制备
Figure imgf000107_0001
N-(4-(6,-Dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3-fluorophenylacetamide Preparation
Figure imgf000107_0001
N-(4-溴 -2,6-二甲基苯基) -3-*** （化合物 133A)  N-(4-bromo-2,6-dimethylphenyl)-3-phenylpropylamine (Compound 133A)
在室温下， 将 4-溴 -2,6-二甲基苯胺 （2 g， 10 mmol)和三乙胺 (2.08 mL， 15 mmol)在二氯甲 烷 (40 mL)中搅拌半个小时，然后将苯丙酰氯 （0.86 g， 12 mmol)逐滴的加入到上述溶液中， 室 温下搅拌过夜。 用水 （lOO mL)淬灭， 分离有机相， 有机相用饱和的食盐水洗涤， 无水硫酸钠 干燥， 旋干， 粗产品用二氯甲烷和石油醚重结晶得到目标产物 (2.5 g，收率 76%)。  4-Bromo-2,6-dimethylaniline (2 g, 10 mmol) and triethylamine (2.08 mL, 15 mmol) were stirred in dichloromethane (40 mL) for half an hour at room temperature then Phenylpropanoyl chloride (0.86 g, 12 mmol) was added dropwise to the above solution and stirred at room temperature overnight. The organic phase was separated with water (100 mL), EtOAc (EtOAc m. 76%).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -2-(3-氟苯基乙酰胺 （化合物 N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3-fluorophenyl) Amide
133 ) 133)
本品由 4，5，6，7-四氢噻吩 [3，2-c]吡啶 （70 mg， 0.5 mmol)和 N-(4-溴 -2,6-二甲基苯基) -3-苯丙 胺 C150 mg， 0.5 mmol) 按照化合物 120的制备方法合成， 纯化得到目标产物 （50 mg， 15 % 收 率）。 MS: 391.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 8.97 (s， 1Η), 7.29 (m, 6H)， 6.91 (d, J=5.2 Hz, 1H)， 6.69 (s， 2H)， 4.23 (s, 2H), 3.54 (t， J=5.2 Hz，2H)， 2.90 (m， 4H)， 2.60 (t， J=7.6 Hz, 2H), 1.90 (s, 6H).  This product consists of 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (70 mg, 0.5 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3- Amphetamine C 150 mg, 0.5 mmol) was synthesized according to the procedure for the preparation of compound 120 and purified to give the desired product (50 mg, 15% yield). MS: 391.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 8.97 (s, 1 Η), 7.29 (m, 6H), 6.91 (d, J=5.2 Hz, 1H), 6.69 (s, 2H ), 4.23 (s, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.90 (m, 4H), 2.60 (t, J = 7.6 Hz, 2H), 1.90 (s, 6H).
实施例一百三十四  Example one hundred thirty four
N-(4-(6，7-二氢噻吩 [3，2-C]吡啶 -5 4H)-基) -2，6-二甲基苯基) -2-(4-氟苯基乙酰胺的制备
Figure imgf000107_0002
N-(4-(6,7-Dihydrothiophene[3,2- C ]pyridine-5 4H)-yl)-2,6-dimethylphenyl)-2-(4-fluorophenylacetamide Preparation
Figure imgf000107_0002
N-(4-溴 -2,6-二甲基苯基) -2-(4-氟苯基)乙酰胺 （化合物 134A)  N-(4-bromo-2,6-dimethylphenyl)-2-(4-fluorophenyl)acetamide (Compound 134A)
在室温下，将 4-溴 -2,6-二甲基苯胺 （1 g, 5.0 mmol)和三乙胺在二氯甲烷中搅拌半个小时， 然后将 2-(4-氟苯基)乙酰氯 （0.86 g， 5.0 mmol)逐滴的加入到上述溶液中， 室温下搅拌过夜。 用水 （lOO mL)淬灭， 分离有机相， 有机相用饱和的食盐水洗涤， 无水硫酸钠干燥， 旋干， 粗 产品用 (二氯甲烷和石油醚)重结晶得到目标产物 (1.0 g， 收率 59%)。  4-Bromo-2,6-dimethylaniline (1 g, 5.0 mmol) and triethylamine were stirred in dichloromethane for half an hour at room temperature, then 2-(4-fluorophenyl) The acid chloride (0.86 g, 5.0 mmol) was added dropwise to the above solution and stirred at room temperature overnight. After quenching with water (100 mL), EtOAc (EtOAc m. Yield 59%).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -2-(4-氟苯基乙酰胺 （化合物 N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(4-fluorophenyl) Amide
134) 本品由 4，5，6，7-四氢噻吩 [3，2-c]吡啶 （139 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯基) -2-(4-氟 苯基)乙酰胺 （336 mg，l mmol)按照化合物 120的制备方法合成， 纯化得到目标产物 （150 mg， 38 % 收率）。 MS: 395.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.25 (s， 1H), 7.40 (m， 2H)， 7.33 (d, J=5.2 Hz, 1H)， 7.18 (t, J=2 Hz, 2H), 6.91 (d, J=4.8 Hz, 1H)， 6.74 (s, 1H), 4.25 (s, 2H), 3.60 (s， 2H)， 3.56 (t， J= 5.6 Hz, 2H), 2.90 (t， J=5.2 Hz, 2H), 2.03 (s， 6H). 134) This product consists of 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (139 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)-2- (4-Fluorophenyl)acetamide (336 mg, 1 mmol) was synthesized according to the procedure of Compound 120 and purified to give the desired product (150 mg, 38% yield). MS: 395.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.25 (s, 1H), 7.40 (m, 2H), 7.33 (d, J = 5.2 Hz, 1H), 7.18 (t, J =2 Hz, 2H), 6.91 (d, J=4.8 Hz, 1H), 6.74 (s, 1H), 4.25 (s, 2H), 3.60 (s, 2H), 3.56 (t, J= 5.6 Hz, 2H ), 2.90 (t, J=5.2 Hz, 2H), 2.03 (s, 6H).
实施例一百三十五  Example one hundred thirty five
N-(4- 6，7-二氢噻吩 [3，2-C]吡啶 -5(4H)-基) -2，6-二甲基苯基) -2-(3-氟苯基乙酰胺的制备
Figure imgf000108_0001
N-(4- 6,7-dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3-fluorophenylacetamide Preparation
Figure imgf000108_0001
2-(3-氟苯基)乙酰氯 （化合物 135A)  2-(3-fluorophenyl)acetyl chloride (Compound 135A)
将 2-(2-氟苯基)乙酸 (1 g, 6.49 mmol) 溶于二氯甲烷 （20 mL) 加入草酰氯 (2.74 mL， 32.44 mmol) 和 （0.2 mL)， 该反应液在室温下搅拌 3小时。旋干后粗产品直接用于下一步反应（ 1 g， 90% 收率）  2-(2-Fluorophenyl)acetic acid (1 g, 6.49 mmol) was dissolved in dichloromethane (20 mL). oxalyl chloride (2.74 mL, 32.44 mmol) and (0.2 mL). 3 hours. After spinning, the crude product is directly used in the next reaction (1 g, 90% yield)
N-(4-溴 -2,6-二甲基苯基) -2-(3-氟苯基)乙酰胺 （化合物 135B)  N-(4-bromo-2,6-dimethylphenyl)-2-(3-fluorophenyl)acetamide (Compound 135B)
在室温下，将 4-溴 -2,6-二甲基苯胺 （1 g, 5.0 mmol)和三乙胺在二氯甲烷中搅拌半个小时， 然后将 2-(4-氟苯基)-乙酰氯 （0.86 g， 5.0 mmol) 逐滴的加入到上述溶液中， 室温下搅拌过夜。 用水 （lOO mL)淬灭， 分离有机相， 有机相用饱和的食盐水洗涤， 无水硫酸钠干燥， 旋干， 粗 产品用二氯甲烷和石油醚重结晶得到目标产物 (1.0 g， 收率 59%)。  4-Bromo-2,6-dimethylaniline (1 g, 5.0 mmol) and triethylamine were stirred in dichloromethane for half an hour at room temperature then 2-(4-fluorophenyl)- Acetyl chloride (0.86 g, 5.0 mmol) was added dropwise to the above solution and stirred at room temperature overnight. Quenched with water (100 mL), EtOAc (EtOAc)EtOAc. 59%).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -2-(3-氟苯基乙酰胺 （化合物 N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3-fluorophenyl) Amide
135 ) 135 )
本品由 4，5，6，7-四氢噻吩 [3，2-c]吡啶 (70 mg， 0.5 mmol)和 N-(4-溴 -2,6-二甲基苯基) -2-(4-氟 苯基)乙酰胺 （170 mg， 0.5 mmol) 按照化合物 120的制备方法合成， 反应结束后， 加入乙酸乙 酯和水，分离有机相，用饱和的食盐水洗涤，旋干后，反相柱色谱分离得到目标产物 （100 mg， 50 % yield)。 MS: 395.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.26 (s， 1H), 7.40 (m， 2H)， 7.33 (d, J=5.2 Hz, 1H)， 7.18 (t, J=2 Hz, 2H), 6.91 (d, J=4.8 Hz, 1H)， 6.72 (s, 1H), 4.24 (s, 2H), 3.69 (s， 2H)， 3.56 (t， J= 5.6 Hz, 2H), 2.90 (t， J=5.2 Hz, 2H), 2.03 (s, 6H)。  This product consists of 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (70 mg, 0.5 mmol) and N-(4-bromo-2,6-dimethylphenyl)-2- (4-Fluorophenyl)acetamide (170 mg, 0.5 mmol) was synthesized according to the preparation method of Compound 120. After completion of the reaction, ethyl acetate and water were added, and the organic phase was separated, washed with saturated brine and dried. The title product (100 mg, 50% yield) was obtained by reverse phase column chromatography. MS: 395.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.26 (s, 1H), 7.40 (m, 2H), 7.33 (d, J = 5.2 Hz, 1H), 7.18 (t, J =2 Hz, 2H), 6.91 (d, J=4.8 Hz, 1H), 6.72 (s, 1H), 4.24 (s, 2H), 3.69 (s, 2H), 3.56 (t, J= 5.6 Hz, 2H ), 2.90 (t, J = 5.2 Hz, 2H), 2.03 (s, 6H).
实施例一百三十六  Example one hundred thirty six
N-(4-(6，7-二氢噻吩 [3，2-C]吡啶 -5(4H)-基) -2，6-二甲基苯基) -2-(2-氟苯基乙酰胺的制备
Figure imgf000109_0001
N-(4-(6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(2-fluorophenyl) Preparation of amide
Figure imgf000109_0001
2-(2-氟苯基)乙酰氯 （化合物 136A) 2-(2-fluorophenyl)acetyl chloride (compound 136A)
将 2-(2-氟苯基)乙酸 (1 g, 6.49 mmol) 溶于二氯甲烷 （20 mL) 加入草酰氯 (2.74 mL， 32.44 mmol) 和 （0.2 mL)， 该反应液在室温下搅拌 3小时。 旋干后粗产品直接用于下一步反应 （1 g， 90%收率）  2-(2-Fluorophenyl)acetic acid (1 g, 6.49 mmol) was dissolved in dichloromethane (20 mL). oxalyl chloride (2.74 mL, 32.44 mmol) and (0.2 mL). 3 hours. After spinning, the crude product was directly used in the next reaction (1 g, 90% yield)
N-(4-溴 -2,6-二甲基苯基) -2-(2-氟苯基)乙酰胺 （化合物 136B)  N-(4-bromo-2,6-dimethylphenyl)-2-(2-fluorophenyl)acetamide (Compound 136B)
在室温下，将 4-溴 -2,6-二甲基苯胺 （1 g, 5.0 mmol)和三乙胺在二氯甲烷中搅拌半个小时， 然后将 2-(4-氟苯基)乙酰氯 （0.86 g， 5.0 mmol)逐滴的加入到上述溶液中， 室温下搅拌过夜。 用水 (100 mL)淬灭， 分离有机相， 有机相用饱和的食盐水洗涤， 无水硫酸钠干燥， 旋干， 粗 产品用二氯甲烷和石油醚重结晶得到目标产物 (1.0 g， 收率 59%)。  4-Bromo-2,6-dimethylaniline (1 g, 5.0 mmol) and triethylamine were stirred in dichloromethane for half an hour at room temperature, then 2-(4-fluorophenyl) The acid chloride (0.86 g, 5.0 mmol) was added dropwise to the above solution and stirred at room temperature overnight. After quenching with water (100 mL), EtOAc (EtOAc)EtOAc. 59%).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基) -2-(2-氟苯基乙酰胺 （化合物 N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(2-fluorophenyl) Amide
136) 136)
本品由 4，5，6，7-四氢噻吩 [3，2-c]吡啶 (70 mg， 0.5 mmol)和 N-(4-溴 -2,6-二甲基苯基) -2-(4-氟 苯基)乙酰胺 （170 mg， 0.5 mmol) 按照化合物 120的制备方法合成， 纯化得到目标产物 （100 mg， 50 % yield)。 MS: 395.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.25 (s， 1H)， 7.40 (m， 2H)， 7.33 (d, J=5.2 Hz, 1H)， 7.18 (t, J=2 Hz, 2H), 6.91 (d，J=4.8 Hz， 1H)， 6.72 (s, 1H), 4.24 (s, 2H), 3.69 (s, 2H)， 3.56 (t， J= 5.6 Hz, 2H), 2.90 (t， J=5.2 Hz, 2H), 2.03 (s, 6H).  This product consists of 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (70 mg, 0.5 mmol) and N-(4-bromo-2,6-dimethylphenyl)-2- (4-Fluorophenyl)acetamide (170 mg, 0.5 mmol) was synthesized according to the procedure for the preparation of compound 120, and purified to give the desired product (100 mg, 50% yield). MS: 395.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.25 (s, 1H), 7.40 (m, 2H), 7.33 (d, J = 5.2 Hz, 1H), 7.18 (t, J =2 Hz, 2H), 6.91 (d, J=4.8 Hz, 1H), 6.72 (s, 1H), 4.24 (s, 2H), 3.69 (s, 2H), 3.56 (t, J= 5.6 Hz, 2H ), 2.90 (t, J=5.2 Hz, 2H), 2.03 (s, 6H).
实施例一百三十七  Example one hundred thirty seven
2-(4-氯苯基) -N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基)乙酰胺 （化合物 137) 的制备
Figure imgf000109_0002
2-(4-Chlorophenyl)-N-(4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl) Preparation of acetamide (compound 137)
Figure imgf000109_0002
氢化钠 (22 mg， 0.581 mmol)分批的加入到 4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲 基苯胺的四氢呋喃 (10 mL)溶液， 该反应液在室温下搅拌 10分钟， 2-(4-氯苯基)乙酰氯 (80 mg， 0.426 mmol)逐滴的加入到上述溶液， 室温下搅拌 3小时， 加入水 （10 mL)淬灭反应， 有机相 用乙酸乙酯萃取， 饱和的食盐水洗涤， 无水硫酸钠干燥， 旋干， 粗产品反相柱色谱分离 (20mg， 收率 12 %)。 MS: 381.3 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.31 (s， 1H), 7.44 (s， 1H)， 7.38 (m，4H)， 6.91 (d， J=4.8 Hz, 1H)， 6.77 (s, 2H), 4.27 (s, 2H), 3.64 (s, 2H),3.58 (t, J=5.6 Hz 2H), 2.92 (s, 2H), 2.04 (s, 6H). Sodium hydride (22 mg, 0.581 mmol) was added portionwise to 4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline Tetrahydrofuran (10 mL) solution, the reaction mixture was stirred at room temperature for 10 minutes, 2-(4-chlorophenyl)acetyl chloride (80 mg, 0.426 mmol) was added dropwise to the above solution, stirred at room temperature for 3 hours, added The reaction was quenched with EtOAc (EtOAc)EtOAc. MS: 381.3 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 9.31 (s, 1H), 7.44 (s, 1H), 7.38 (m, 4H), 6.91 (d, J = 4.8 Hz, 1H), 6.77 (s, 2H), 4.27 (s, 2H), 3.64 (s, 2H), 3.58 (t, J = 5.6 Hz 2H), 2.92 (s, 2H), 2.04 (s, 6H).
实施例一百三十八  Example one hundred thirty eight
2-(3-溴苯) -N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基)乙酰胺（化合物 138 ) 的制备
Figure imgf000110_0001
2-(3-Bromobenzene)-N-(4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl) Preparation of amide (compound 138)
Figure imgf000110_0001
2-(3-溴苯)乙酸 （173 mg， 0.8 mmol) 溶解于二氯甲烷 （10 mL)中， 冰浴下滴加草酰氯 (0.08 mL, 0.89 mmol), 滴毕室温搅拌半小时， 旋干溶剂， 剩余物溶于四氢呋喃 (2 mL)， 然后 冰浴下滴加到 4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯胺 （173 mg， 0.67 mmol)和 三乙胺 (242 mg， 2.4 mmol) 的四氢呋喃（8 mL)溶液中， 滴毕， 室温搅拌 1.5小时。减压浓縮， 剩余物溶于乙酸乙酯 （100 mL)中， 分别用水和饱和食盐水洗涤一次， 无水硫酸钠干燥后， 减 压浓縮，剩余物制备分离的到纯的化合物 138(80 mg， 26%)，黄色固体。 LCMS: [M+l]+:455; 1H NMR (COCh-d, 400MHz): δ 7.58 (s, 1Η), 7.81 (d, J= 8.8 Hz, 1H), 7.48 (s, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H)， 7.28 (m， 1H)， 7.13 (m， 2H), 6.83 (d, J = 5.2 Hz, 1H )， 6.68 (s， 1H)， 6.54 (s, 1H), 4.27 (s, 2H), 3.75 (s, 2H), 3.58 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 2.12 (s, 6H). 2-(3-Bromophenyl)acetic acid (173 mg, 0.8 mmol) was dissolved in dichloromethane (10 mL). oxalyl chloride (0.08 mL, 0.89 mmol) was added dropwise in an ice bath, and stirred at room temperature for half an hour. Dry solvent, the residue was dissolved in tetrahydrofuran (2 mL), then added dropwise to 4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6 A solution of dimethylaniline (173 mg, 0.67 mmol) and triethylamine (242 mg, 2.4 mmol) in tetrahydrofuran (8 mL) was evaporated. The residue was dissolved in ethyl acetate (100 mL). EtOAc (EtOAc) 80 mg, 26%), yellow solid. LCMS: [M+l] + : 455; 1H NMR (COCh-d, 400 MHz): δ 7.58 (s, 1 Η), 7.81 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.49 ( d, J = 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 (m, 1H), 7.13 (m, 2H), 6.83 (d, J = 5.2 Hz, 1H ), 6.68 ( s, 1H), 6.54 (s, 1H), 4.27 (s, 2H), 3.75 (s, 2H), 3.58 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 2.12 (s, 6H).
实施例一百三十九  Example one hundred thirty nine
N-(4-(6，7-二氢噻吩 3，2-C]吡啶 -5(4氢) -基) -2，6-二甲基苯基 -2- (间苯)乙酰胺的制备
Figure imgf000110_0002
Preparation of N-(4-(6,7-dihydrothiophene 3,2- C ]pyridine-5(4-hydro)-yl)-2,6-dimethylphenyl-2-(m-phenyl)acetamide
Figure imgf000110_0002
N-(4-溴 -2,6-二甲基苯基) -2- (间苯)乙酰胺 （化合物 139A)  N-(4-bromo-2,6-dimethylphenyl)-2-(m-phenyl)acetamide (compound 139A)
本品由 2- (间苯)乙酸 （3.0 g， 20 mmol)按照化合物 138的制备方法合成， 纯化得化合物 139A(4.2 g, 64%) ， 黄色固体。  This product was synthesized from 2-(m-phenyl)acetic acid (3.0 g, 20 mmol) according to Compound 138. Compound 139A (4.2 g, 64%)
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4氢) -基) -2,6-二甲基苯基 -2- (间苯)乙酰胺 （化合物 139) 本品由化合物 139A (331 mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (139 mg， 1.0 mmol) 按照化合物 120的制备方法合成，氮气保护下在甲苯 (10 mL)中回流搅拌两小时，得化合物 139 (200 mg， 51%), 黄色固体。 LCMS: [M+l]+:391; 1H NMR (CDC13- , 400ΜΗζ): δ 7.58 (s, 1H)， 7.30 (m， 1H)， 7.21 (m， 4H)， 6.83 (d, J= 5.2 Hz, 1H)， 6.69 (s, 2H), 6.49 (s, 1H)， 4.27 (s, 2H), 3.76 (s: 2H), 3.58 (t， J= 5.6 Hz, 2H), 2.98 (m， 2H), 2.40 (s， 3H), 2.12 (s， 6H). 实施例一百四十 N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4-hydro)-yl)-2,6-dimethylphenyl-2-(m-phenyl)acetamide ( Compound 139) This product was prepared from compound 139A (331 mg, 1.0 mmol) and s. 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (139 mg, 1.0 mmol) according to compound 120 the method of synthesis, stirred for two hours under nitrogen in toluene (10 mL) at reflux to give compound 139 (200 mg, 51%) , as a yellow solid LCMS: [M + l] + : 391; 1H NMR (CDC1 3 -,. 400ΜΗζ): δ 7.58 (s, 1H), 7.30 (m, 1H), 7.21 (m, 4H), 6.83 (d, J= 5.2 Hz, 1H), 6.69 (s, 2H), 6.49 (s, 1H) , 4.27 (s, 2H), 3.76 (s : 2H), 3.58 (t, J = 5.6 Hz, 2H), 2.98 (m, 2H), 2.40 (s, 3H), 2.12 (s, 6H). Example one hundred forty
N-(4-(6，7-二氢噻吩并 [3，2-c]吡啶 -5(4 氢) -基) -2,6-二甲苯基) -2-(3-甲氧基苯基)乙酰胺 （化 合物 140) 的制备
Figure imgf000111_0001
N-(4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4-hydro)-yl)-2,6-dimethylphenyl)-2-(3-methoxybenzene Preparation of acetamide (compound 140)
Figure imgf000111_0001
本品由 2-(3-甲氧基苯)乙酸 （199 mg， 1.2mmol) 按照化合物 138的制备方法合成，纯化得 产品（160mg，40%)， 黄色固体。 LCMS: [M+l]+:407.1H NMR (COCh-d, 400MHz): δ 7.37 (t, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.13 (d,J= 5.2 Hz, 1H), 7.00 (d,J= 8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (dd， J= 5.2 Hz, 2.0 Hz, 1H)， 6.83 (d,J= 5.2 Hz, 1H)， 6.67 (d,J= 5.2 Hz, 2H), 6.53 (s, 1H)， 4.27 (s, 2H): 3.85 (s, 3H), 3.76 (d, J= 8.8 Hz，， 2H), 3.58 (t， J= 5.2 Hz, 2H), 2.98 (t, J= 5.2 Hz, 2H), 2.12 (s, 6H). This product was synthesized from 2-(3-methoxyphenyl)acetic acid (199 mg, 1.2 mmol) according to the procedure of compound 138 to afford product (160 mg, 40%) as a yellow solid. LCMS: [M+l] + : 407.1H NMR (COCh-d, 400MHz): δ 7.37 (t, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.13 (d, J = 5.2 Hz, 1H ), 7.00 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (dd, J = 5.2 Hz, 2.0 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 6.67 ( d, J = 5.2 Hz, 2H), 6.53 (s, 1H), 4.27 (s, 2H) : 3.85 (s, 3H), 3.76 (d, J= 8.8 Hz,, 2H), 3.58 (t, J= 5.2 Hz, 2H), 2.98 (t, J= 5.2 Hz, 2H), 2.12 (s, 6H).
实施例一百四 ^一  Embodiment one hundred four ^ one
N-(4-(6，7-二氢噻吩并 [3，2-C]吡啶 -5(4 氢) -基) -2，6-二甲苯基) -2-(3-三氟甲基)乙酰胺 （化合 物 141) 的制备
Figure imgf000111_0002
N-(4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4-hydro)-yl)-2,6-dimethylphenyl)-2-(3-trifluoromethyl) Preparation of acetamide (compound 141)
Figure imgf000111_0002
本品由 2-(3-三氟甲基)乙酸 （245 mg， 1.2mmol) 按照化合物 138的制备方法合成，纯化得 产物 (120 mg, 27%),黄色固体。 LCMS: [M+l]+:445.1HNMR (CDC13- , 400ΜΗζ): δ 7.69 (s， 1Η)， 7.62 (d,J= 7.6Hz, 2Η), 7.56 (d,J= 7.2Ηζ, 1Η), 7.39 (d,J= 6.0 Hz, 1H), 7.14 (d,J= 5.2 Hz, 1H)， 6.84 (d， J= 4.8 Hz, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 6.52 (s, 1H), 4.27 (s, 2H), 3.84 (s, 2H), 3.59 (t，J = 5.6 Hz, 2H), 2.98 (t,J= 5.2 Hz, 2H), 2.12 (s， 6H). This product was synthesized from 2-(3-trifluoromethyl)acetic acid (245 mg, 1.2 mmol. LCMS: [M+l] + : 445.1HNMR (CDC1 3 - , 400 ΜΗζ): δ 7.69 (s, 1 Η), 7.62 (d, J = 7.6 Hz, 2 Η), 7.56 (d, J = 7.2 Ηζ, 1 Η) , 7.39 (d, J = 6.0 Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 6.84 (d, J = 4.8 Hz, 1H), 6.73 (s, 1H), 6.69 (s, 1H) , 6.52 (s, 1H), 4.27 (s, 2H), 3.84 (s, 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.98 (t, J = 5.2 Hz, 2H), 2.12 (s, 6H).
实施例一百四十二  Example one hundred and forty two
2-(3，5-二氟苯基) -N-(4-(6，7-二氢噻吩并 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲苯基)乙酰胺 （化合 物 142) 的制备
Figure imgf000111_0003
2-(3,5-difluorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-xylene Preparation of acetamide (Compound 142)
Figure imgf000111_0003
本品由 2-03,5-二氟苯)乙酸 C206mg， 1.2mmol) 按照化合物 138的制备方法合成，纯化得 化合物 142(100 mg， 24%)， 黄色固体。 LCMS: [M+l]+:413.1H NMR (CDCI3- , 400ΜΗζ): δ 7.14 (d， J= 5.2Hz, 1H)， 6.97 (d, J= 6.0Hz, 2H), 6.85 (d, J= 5.2Hz, 2H), 6.74 (s, 2H), 6.62 (m， 1H)， 4.29 (s, 2H), 3.76 (s, 2H), 3.60 (t, J= 5.6 Hz, 2H), 2.98 (t, J= 5.2 Hz, 2H), 2.13 (s, 6H). This product was synthesized from 2-03,5-difluorophenyl)acetic acid C 206 mg (1.2 mmol) according to the procedure of Compound 138. Compound 142 (100 mg, 24%) LCMS: [M+l] + : 413.1H NMR (CDCI3-, 400 ΜΗζ): δ 7.14 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 6.0 Hz, 2H), 6.85 (d, J = 5.2 Hz, 2H), 6.74 (s, 2H), 6.62 (m, 1H), 4.29 (s, 2H), 3.76 (s, 2H), 3.60 (t, J = 5.6 Hz, 2H), 2.98 (t, J = 5.2 Hz, 2H), 2.13 (s, 6H).
实施例一百四十三  Example one hundred forty three
2-(2，4-二氯苯基) -氮 -(4-(6，7-二氢噻吩并 [3，2-C]吡啶 -5(4H)-基) -2，6-二甲苯基)乙酰胺的制 备
Figure imgf000112_0001
2-(2,4-dichlorophenyl)-nitro-(4-(6,7-dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-xylene Preparation of acetamide
Figure imgf000112_0001
N-(4-溴 -2,6-二甲苯基) -2-(2，4-二氯苯基)乙酰胺 （化合物 143A)  N-(4-bromo-2,6-dimethylphenyl)-2-(2,4-dichlorophenyl)acetamide (compound 143A)
本品由 2-(2，4-二氯苯)乙酸 （4.10 g， 20 mmol) 按照化合物 138的制备方法合成，纯化得化 合物 143A(3.8 g， 49%), 黄色固体。  This product was synthesized from 2-(2,4-dichlorobenzene)acetic acid (4.10 g, 20 mmol) according to Compound 138. Compound 143A (3.8 g, 49%)
2-(2，4-二氯苯基) -氮 -(4-(6，7-二氢噻吩并 [3，2-C]吡啶 -5(4H)-基) -2,6-二甲苯基)乙酰胺 （化合 物 143 ) 2-(2,4-dichlorophenyl)-nitro-(4-(6,7-dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-xylene Acetamide (compound 143)
本品由化合物 143A (385 mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (139 mg， 1.0 mmol) 按照化合物 120的制备方法合成，氮气保护下在甲苯 (10 mL)中回流搅拌两小时，得化合物 143 (30 mg， 7%),黄色固体。 LCMS: [M+l]+:445. 1H NMR (COCh-d, 400MHz): δ 7.50 (s, 1H)， 7.43 (d: J= 8.0 Hz, 1H)， 7.32 (d, J= 7.6 Hz, 1H), 7.14 (d, J= 4.4 Hz, 1H), 6.83 (d，J= 4.8 Hz， 1H), 6.70 (s, 2H), 6.66 (s， 1H), 4.28 (s， 2H), 3.88 (s， 2H), 3.59 (t， J= 5.6 Hz, 2H), 2.98 (m， 2H), 2.12 (s， 6H). 实施例一百四十四 This product is synthesized from compound 143A (385 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (139 mg, 1.0 mmol) according to the preparation method of compound 120. Stirring under toluene (10 mL) for two hours under nitrogen to give compound 143 (30 mg, 7%) as a yellow solid. LCMS: [M+l] + : 445. 1H NMR (COCh-d, 400 MHz): δ 7.50 (s, 1H), 7.43 (d : J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.14 (d, J= 4.4 Hz, 1H), 6.83 (d, J= 4.8 Hz, 1H), 6.70 (s, 2H), 6.66 (s, 1H), 4.28 (s, 2H), 3.88 ( s, 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.98 (m, 2H), 2.12 (s, 6H). Example one hundred forty four
2-(3，4-二氯苯基 -N-(4-(6，7-二氢噻吩并 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲苯基)乙酰胺的制备
Figure imgf000112_0002
2-(3,4-Dichlorophenyl-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl Preparation of acetamide
Figure imgf000112_0002
N-(4-溴 -2,6-二甲苯基) -2-(3，4-二氯苯基)乙酰胺 （化合物 144A)  N-(4-bromo-2,6-dimethylphenyl)-2-(3,4-dichlorophenyl)acetamide (Compound 144A)
本品由 2-(3，4-二氯苯)乙酸 （4.10 g， 20 mmol) 按照化合物 138的制备方法合成，纯化得化 合物 144A(4.0 g， 52%), 黄色固体。  This product was synthesized from 2-(3,4-dichlorophenyl)acetic acid (4.10 g, 20 mmol) according to Compound 138. Compound 144A (4.0 g, 52%).
2-(3，4-二氯苯基) -氮 -(4-(6，7-二氢噻吩并 [3，2-C]吡啶 -5(4H)-基) -2,6-二甲苯基)乙酰胺 （化合 物 144) 2-(3,4-dichlorophenyl)-nitro-(4-(6,7-dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-xylene Acetylamine (compound 144)
本品由化合物 144A (385 mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (139 mg， 1.0 mmol) 按照化合物 120的制备方法合成， 氮气保护下在甲苯 (10 mL)中回流搅拌两小时， 得到化合物 144(100 mg， 23%), 黄色固体。 LCMS: [M+l]+:445. 1H NMR ( DC -d, 400MHz): δ 7.53 (d， J = 2.0 Hz, 1H)， 7.49 (d， J = 8.4 Hz, 1H)， 7.14 (d， J = 5.2 Hz, 1H)， 7.01 (s， 1H)， 6.84 (d, J = 5.2 Hz 1H), 6.74 (s， 2H), 6.69 (s， 1H), 4.28 (s， 2H), 3.73 (s， 2H), 3.59 (t， J = 5.6 Hz, 2H), 2.98 (m， 2H), 2.12 (s, 6H). This product is synthesized from compound 144A (385 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (139 mg, 1.0 mmol) according to the preparation method of compound 120. Stirring under toluene (10 mL) under nitrogen for two hours afforded compound 144 (100 mg, 23%) as a yellow solid. LCMS: [M+l] + : 445. 1H NMR (DC -d, 400 MHz): δ 7.53 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 7.01 (s, 1H), 6.84 (d, J = 5.2 Hz 1H), 6.74 ( s, 2H), 6.69 (s, 1H), 4.28 (s, 2H), 3.73 (s, 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.98 (m, 2H), 2.12 (s, 6H) ).
实施例一百四十五  Example one hundred forty five
2-(2，6-二氯 基) -N-(4-(6，7-二氢噻吩并 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲苯基)乙酰胺的制备
Figure imgf000113_0001
2-(2,6-dichloro)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl Preparation of acetamide
Figure imgf000113_0001
N-(4-溴 -2,6-二甲苯基) -2-(2，6-二氯苯基)乙酰胺 （化合物 145A)  N-(4-bromo-2,6-dimethylphenyl)-2-(2,6-dichlorophenyl)acetamide (Compound 145A)
本品由 2-(2，6-二氯苯)乙酸 （4.10 g， 20 mmol) 按照化合物 138的制备方法合成，纯化得化 合物 145AC3.7 g， 48%) ， 黄色固体。  This product was synthesized from 2-(2,6-dichlorophenyl)acetic acid (4.10 g, 20 mmol) according to the procedure of Compound 138, to yield compound 145AC 3.7 g, 48%) as a yellow solid.
2-(2，6-二氯苯基) -N-(4-(6，7-二氢噻吩并 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲苯基)乙酰胺 （化合 物 145 )  2-(2,6-dichlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-xylene Acetylamine (compound 145)
本品由化合物 145A (385 mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (139 mg， 1.0 mmol) 按照化合物 120的制备方法合成，氮气保护下在甲苯 (10 mL)中回流搅拌两小时，得化合物 145 (80 mg， 18%), 黄色固体。 LCMS: [M+l]+:445. 1H NMR (COCh-d, 400ΜΗζ): δ 7.7.32 (d， J= 8.0 Hz, 2H), 7.16 (t， J = 8.4 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.73 (d， J = 5.2 Hz, 1H), 6.60 (s， 2H), 4.15 (s, 2H), 3.86 (s, 2H), 3.47 (t, J= 5.6 Hz, 2H), 2.86 (t, J= 5.6 Hz, 2H),， 2.29 (s, 6H). This product is synthesized from compound 145A (385 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (139 mg, 1.0 mmol) according to the preparation method of compound 120. Stirring under toluene (10 mL) for two hours under nitrogen to afford compound 145 (80 mg, 18%) LCMS: [M+l] + : 445. 1H NMR (COCh-d, 400 ΜΗζ): δ 7.7.32 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 8.4 Hz, 1H), 7.03 ( d, J = 5.2 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 6.60 (s, 2H), 4.15 (s, 2H), 3.86 (s, 2H), 3.47 (t, J= 5.6 Hz, 2H), 2.86 (t, J= 5.6 Hz, 2H),, 2.29 (s, 6H).
实施例一百四十六  Example one hundred forty six
N-(4-(6，7-二氢噻吩 3，2-c]吡啶 -5(4氢) -基) -2，6-二甲基苯基 -2-(2，5-二甲苯基)乙酰胺的制备
Figure imgf000113_0002
N-(4-(6,7-Dihydrothiophene 3,2-c]pyridine-5(4-hydro)-yl)-2,6-dimethylphenyl-2-(2,5-dimethylphenyl) Preparation of acetamide
Figure imgf000113_0002
N-(4-溴 -2,6-二甲基苯基) -2-(2，5-二甲苯基)乙酰胺 （化合物 146A) N- (4-bromo-2,6-dimethylphenyl)-2-(2,5-dimethylphenyl)acetamide (Compound 146A)
本品由 2- (间苯)乙酸 （3.32 g， 20 mmol) 按照化合物 138的制备方法合成， 纯化得化合物 146A(3.8 g, 55%) ， 黄色固体。  This product was synthesized from 2-(m-phenyl)acetic acid (3.32 g, 20 mmol) according to Compound 138. Compound 146A (3.8 g, 55%)
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4氢) -基) -2,6-二甲基苯基 -2-(2，5-二甲苯基)乙酰胺 （化合 物 146)  N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4-hydro)-yl)-2,6-dimethylphenyl-2-(2,5-xylene Acetylamine (compound 146)
本品由化合物 146A (345 mg， 1.0 mmol)禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (139 mg， 1.0 mmol) 按照化合物 120的制备方法合成，氮气保护下在甲苯 (10 mL)中回流搅拌两小时，得化合物 146 (200 mg， 50%), 黄色固体。 LCMS: [M+l]+:405; 1H NMR ( DC -d, 400MHz): δ 7.16 (m， 3H), 7.08 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 5.6 Hz, 1H), 6.69 (m, 2H), 6.45 (s, 1H), 4.27 (s, 2H), 3.76 (s, 2H), 3.58 (t, J= 5.6 Hz, 2H), 2.98 (m， 2H), 2.40 (s， 3H), 2.36 (s， 1H), 2.12 (s， 6H). This product is synthesized from compound 146A (345 mg, 1.0 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (139 mg, 1.0 mmol) according to the preparation method of compound 120. Stirring under toluene (10 mL) under nitrogen for two hours gave compound 146 (200 mg, 50%) as a yellow solid. LCMS: [M+l] + : 405; 1H NMR (CD - s, 400 MHz): δ 7.16 (m, 3H), 7.08 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 5.6 Hz, 1H), 6.69 (m, 2H), 6.45 (s, 1H), 4.27 (s, 2H), 3.76 (s, 2H ), 3.58 (t, J = 5.6 Hz, 2H), 2.98 (m, 2H), 2.40 (s, 3H), 2.36 (s, 1H), 2.12 (s, 6H).
实施例一百四十七  Example one hundred forty seven
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -2- (3,4-二甲氧基苯基） 乙酰 胺的制
Figure imgf000114_0001
N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3,4-dimethyl Oxyphenyl) acetamide
Figure imgf000114_0001
2- (3,4-二甲氧基苯基） 乙酰氯 （化合物 147A)  2-(3,4-Dimethoxyphenyl)acetyl chloride (Compound 147A)
将化合物 2-(3，4-二甲氧基苯基)乙酸（4.00 g, 0.02 mol)溶于 60 mL无水二氯甲烷溶液中， 滴加 1滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯 （7.62 g， 0.06 mol)。 15分钟 后滴加完毕， 升至室温搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 147A, 未经纯化直接用于下一步反应。  The compound 2-(3,4-dimethoxyphenyl)acetic acid (4.00 g, 0.02 mol) was dissolved in 60 mL of anhydrous dichloromethane and 1 drop of N,N-dimethylformamide was added dropwise. Oxalyl chloride (7.62 g, 0.06 mol) was added dropwise at 0 °C under a nitrogen atmosphere. After 15 minutes, the dropwise addition was completed, and the mixture was stirred at room temperature for 1 hour, and dichloromethane and the residue of oxalyl chloride were evaporated to give crude compound 147A.
N- (4-溴 -2,6-二 甲基苯基） -2- (3,4-二甲氧基苯基） 乙酰胺 （化合物 147B)  N-(4-Bromo-2,6-dimethylphenyl)-2-(3,4-dimethoxyphenyl)acetamide (Compound 147B)
将化合物 4-溴 -2,6-二甲基苯胺 （4.00 g， 0.02 mol) 溶于 80 mL无水二氯甲烷中， 加入三 乙胺 （8.10 g， 0.08 mol)， 0 °C下滴加化合物 147A的无水二氯甲烷溶液 （20 mL)， 20分钟后 滴加完毕。 氮气保护下室温搅拌反应 2小时， 大量沉淀产生， 过滤， 用少量干燥的二氯甲烷 洗涤， 干燥得化合物 147B ( 1.45 g， 19%收率）。 MS: 378 (M+H+). The compound 4-bromo-2,6-dimethylaniline (4.00 g, 0.02 mol) was dissolved in 80 mL of anhydrous dichloromethane, triethylamine (8.10 g, 0.08 mol) was added, and the mixture was added dropwise at 0 °C. A solution of Compound 147A in anhydrous dichloromethane (20 mL) was added dropwise after 20 min. The reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere, and a large portion of precipitate was formed, which was filtered, washed with a small dry methylene chloride and dried to give compound 147B (1.45 g, 19% yield). MS: 378 (M+H + ).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -2- (3,4-二甲氧基苯基） 乙酰 胺 （化合物 147)  N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3,4-dimethyl Oxyphenyl) acetamide (compound 147)
本品由化合物 147B (599 mg， 1.58 mmol) 禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (200 mg, 1.44 mmol)按照化合物 120的制备方法合成， 氮气保护下 120 °C搅拌 2小时得产物， 为白色固体 ( 115 mg， 18%收率）。 MS: 437.2 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.11-7.12 (d, J= 5.2 Hz, 1H), 6.87-6.94 (m， 3H)， 6.81-6.82 (d，J= 5.2 Hz, 1H)， 6.67 (s， 2H), 6.53 (s， 1H), 4.25 (s， 2H), 3.90 (s， 6H)， 3.72 (s， 2H),3.55-3.58 (t， Ji = 6 Hz, J2 = 5.6 Hz, 2H), 2.96 (s， 2H), 2.10 (s， 6H). This product is synthesized from compound 147B (599 mg, 1.58 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (200 mg, 1.44 mmol) according to the preparation method of compound 120. The product was obtained by stirring at 120 ° C for 2 hours under nitrogen to give a white solid (yield: 115 mg, 18% yield). MS: 437.2 (M+H+). 1H NMR (400 MHz, CDC1 3 ) δ: 7.11-7.12 (d, J = 5.2 Hz, 1H), 6.87-6.94 (m, 3H), 6.81-6.82 (d, J = 5.2 Hz, 1H), 6.67 (s, 2H), 6.53 (s, 1H), 4.25 (s, 2H), 3.90 (s, 6H), 3.72 (s, 2H), 3.55-3.58 (t, Ji = 6 Hz, J 2 = 5.6 Hz, 2H), 2.96 (s, 2H), 2.10 (s, 6H).
实施例一百四十八  Example one hundred forty eight
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基)- 2，4，6-三甲基苯乙酰胺的制 备
Figure imgf000114_0002
2，4，6-三甲基苯乙酰氯 （化合物 148A) N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2,4,6-trimethyl Preparation of phenylacetamide
Figure imgf000114_0002
2,4,6-trimethylphenylacetyl chloride (compound 148A)
将化合物 2，4，6-三甲基苯乙酸 （2.50 g， 0.014 mol) 溶于 40 mL无水二氯甲烷溶液中， 滴 加 1滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯 （5.33 g， 0.042 mol)。 15分钟后 滴加完毕， 升至试问搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 148A, 未 经纯化直接用于下一步反应。  The compound 2,4,6-trimethylphenylacetic acid (2.50 g, 0.014 mol) was dissolved in 40 mL of anhydrous dichloromethane, and 1 drop of N,N-dimethylformamide was added dropwise under nitrogen. Oxalyl chloride (5.33 g, 0.042 mol) was added dropwise at 0 °C. After 15 minutes, the dropwise addition was completed, and the mixture was stirred for 1 hour. The dichloromethane and the residue of oxalyl chloride were evaporated to give crude compound 148A.
N- (4-溴 -2,6-二 甲基 苯基） -2，4，6-三甲基苯乙酰胺 （化合物 148B)  N-(4-Bromo-2,6-dimethylphenyl)-2,4,6-trimethylphenylacetamide (Compound 148B)
将化合物 4-溴 -2,6-二甲基苯胺 （2.80 g， 0.014 mol) 溶于 70 mL无水二氯甲烷中， 加入三 乙胺 （5.67 g， 0.056 mol), 0 °C下滴加化合物 148A的无水二氯甲烷溶液 （10 mL), 10分钟 后滴加完毕。 氮气保护下室温搅拌反应 2小时， 大量沉淀产生， 过滤， 用少量干燥的二氯甲 烷洗涤， 干燥得化合物 148B (4.00 g， 79%收率）。 MS: 360.3 (M+H+). The compound 4-bromo-2,6-dimethylaniline (2.80 g, 0.014 mol) was dissolved in 70 mL of anhydrous dichloromethane, triethylamine (5.67 g, 0.056 mol) was added, and the mixture was added dropwise at 0 °C. Compound 148A in anhydrous dichloromethane (10 mL) was added dropwise after 10 min. The reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere, and a large portion of precipitate was formed, which was filtered, washed with a little dry methylene chloride and dried to afford compound 148B (4.00 g, 79% yield). MS: 360.3 (M+H + ).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基)- 2，4，6-三甲基苯乙酰胺 （化 合物 148)  N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2,4,6-trimethyl Phenylacetamide (compound 148)
本品由化合物 148B (569 mg， 1.58 mmol) 禾卩 4，5，6，7-四氢噻吩 [3，2-c]口比啶 (200 mg, 1.44 mmol)按照化合物 120的制备方法合成， 氮气保护下 120 °C搅拌 2小时得化合物 148， 为白 色固体（120 mg，20%收率） 。 MS: 419.3 M+H+). 1H NMR (400 MHz，CDCl3) S: 7.09-7.10 (d，J = 5.2 Hz, 1H)， 6.92 (s, 2H), 6.78-6.80 (d, J= 5.2 Hz, 1H)， 6.63 (s, 2H), 6.43 (s, 1H)， 4.22 (s, 2H), 3.76 (s， 2H), 3.52-3.54 (t， Ji = 5.6 Hz, J2 = 6 Hz, 2H), 2.93 (s， 2H), 2.37 (s， 6H)， 2.27 (s， 3H), 2.09 (s， 6H). This product is synthesized from compound 148B (569 mg, 1.58 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridinium (200 mg, 1.44 mmol) according to the preparation method of compound 120. Stirring at 120 ° C for 2 hours under nitrogen to give compound 148 as a white solid (120 mg, 20% yield). MS: 419.3 M+H + ). 1H NMR (400 MHz, CDCl 3 ) S: 7.09-7.10 (d,J = 5.2 Hz, 1H), 6.92 (s, 2H), 6.78-6.80 (d, J = 5.2 Hz, 1H), 6.63 (s, 2H), 6.43 (s, 1H), 4.22 (s, 2H), 3.76 (s, 2H), 3.52-3.54 (t, Ji = 5.6 Hz, J 2 = 6 Hz, 2H), 2.93 (s, 2H), 2.37 (s, 6H), 2.27 (s, 3H), 2.09 (s, 6H).
实施例一百四十九  Example one hundred forty nine
N- (4- (6，7-二氢噻吩[3，2-0|-5(4¾-基） -2，6-二甲氧基苯基） -2-(2，4，5-三氟苯基)乙酰胺的 制备
Figure imgf000115_0001
N-(4-(6,7-Dihydrothiophene [3,2-0|-5(43⁄4-yl)-2,6-dimethoxyphenyl)-2-(2,4,5-tri) Preparation of fluorophenyl)acetamide
Figure imgf000115_0001
2- (2，4，5-三氟苯基） 乙酰氯 （化合物 149A)  2-(2,4,5-trifluorophenyl)acetyl chloride (compound 149A)
将化合物 2，4，5-三氟苯基乙酸（228 mg, 1.20 mmo)溶于 5mL无水二氯甲烷溶液中， 滴加 1滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯 （305 mg， 2.40 mmol )。 1分钟后滴 加完毕， 升至室温搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 149A, 未经 纯化直接用于下一步反应。  The compound 2,4,5-trifluorophenylacetic acid (228 mg, 1.20 mmo) was dissolved in 5 mL of anhydrous dichloromethane, and 1 drop of N,N-dimethylformamide was added dropwise under nitrogen. Oxalyl chloride (305 mg, 2.40 mmol) was added dropwise at 0 °C. After 1 minute, the dropwise addition was completed, and the mixture was stirred at room temperature for 1 hour, and dichloromethane and the residue of oxalyl chloride were obtained to afford crude compound 149A.
N- (4- (6,7-二氢噻吩 [3，2-c]-5(4H)-基） -2,6-二甲氧基苯基） -2-(2，4，5-三氟苯基)乙酰胺（化 合物 149B) N-(4-(6,7-Dihydrothiophene[3,2-c]-5(4H)-yl)-2,6-dimethoxyphenyl)-2-(2,4,5- Trifluorophenyl)acetamide Compound 149B)
将化合物 4- (6,7-二氢噻吩 [3，2-c]-5(4H)-基） -2,6-二甲氧基苯胺 （235 mg， 0.91 mmol) 溶 于 5 mL无水二氯甲烷中， 加入三乙胺 （507 mg， 5.01 mmol), 0 °C下滴加化合物 149A的无 水二氯甲烷溶液（2 mL)。滴加完毕，氮气保护下室温搅拌反应 1小时，加水， 二氯甲烷萃取， 合并， 干燥， 经制备纯化得化合物 149B (55 mg， 14%收率）。 MS: 431.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 7.20-7.27 (m， 1H), 7.13-7.18 (m， 1H), 6.84-6.89 (m，lH)， 6.65-6.75 (m， 3H), 4.28 (s, 2H )， 3.72 (s,2H), 3.58-3.69 (m， 2H), 2.97-3.04 (m， 2H), 2.15 (s, 6H). Dissolve the compound 4-(6,7-dihydrothiophene[3,2-c]-5(4H)-yl)-2,6-dimethoxyaniline (235 mg, 0.91 mmol) in 5 mL anhydrous Triethylamine (507 mg, 5.01 mmol) was added to dichloromethane, and a solution of Compound 149A in dichloromethane (2 mL). After completion of the dropwise addition, the reaction was stirred at room temperature under nitrogen for 1 hour, water was added, extracted with dichloromethane, combined, dried and purified to afford compound 149B (55 mg, 14% yield). MS: 431.2 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 7.20-7.27 (m, 1H), 7.13-7.18 (m, 1H), 6.84-6.89 (m,lH), 6.65 -6.75 (m, 3H), 4.28 (s, 2H), 3.72 (s, 2H), 3.58-3.69 (m, 2H), 2.97-3.04 (m, 2H), 2.15 (s, 6H).
实施例一百五十  Example one hundred and fifty
N-(4- 6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -2-五氟苯乙酰胺的制备
Figure imgf000116_0001
Preparation of N-(4- 6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-pentafluorophenylacetamide
Figure imgf000116_0001
2-五氟苯乙酰氯 （化合物 150A)  2-pentafluorophenylacetyl chloride (Compound 150A)
将化合物 2-五氟苯乙酸 （271 mg， 1.20 mmol) 溶于 5 mL无水二氯甲烷溶液中， 滴加 1 滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯（305 mg， 2.40 mmol )。 1分钟后滴加 完毕， 升至试问搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 150A, 未经纯 化直接用于下一步反应。  Dissolve the compound 2-pentafluorophenylacetic acid (271 mg, 1.20 mmol) in 5 mL of anhydrous dichloromethane, add 1 drop of N,N-dimethylformamide, and protect with nitrogen at 0 °C. Add oxalyl chloride (305 mg, 2.40 mmol). After 1 minute, the dropwise addition was completed, and the reaction was stirred for 1 hour. The dichloromethane and the remaining oxalyl chloride were evaporated to give the crude compound 150A, which was used for the next reaction without purification.
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -2-五氟苯乙酰胺（化合物 150) 将化合物 N-4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯胺（310 mg， 1.20 mmol) 溶于 5 mL无水二氯甲烷中， 加入三乙胺 （86 mg， 4.8 mmol), 0 °C下滴加化合物 150A的无 水二氯甲烷溶液（2 mL)。滴加完毕，氮气保护下室温搅拌反应 1小时，加水， 乙酸乙酯萃取， 干燥，经制备纯化得产物（55 mg， 10%收率）。 MS: 467.2 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.40 (s, 1H), 7.32-7.33 (d, J= 5.2 Hz, 1H), 6.91-6.92 (d， J= 5.2 Hz, 1H) ， 6.73 (s, 2H), 4.24 (s, 2H )， 3.85 (s,2H), 3.55-3.58 (t， Ji = 5.6 Hz, J2 = 6.0 Hz, 2H), 2.89 (s， 2H), 2.10 (s， 6H). N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-pentafluorophenylacetamide (compound) 150) Dissolve the compound N-4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (310 mg, 1.20 mmol) To 5 mL of anhydrous dichloromethane, triethylamine (86 mg, 4.8 mmol) was added, and a solution of compound 150A in methylene chloride (2 mL) was added dropwise at 0 °C. After completion of the dropwise addition, the reaction was stirred at room temperature under nitrogen for 1 hour, water was added, ethyl acetate was evaporated, and dried, and the product was purified (55 mg, 10% yield). MS: 467.2 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.40 (s, 1H), 7.32-7.33 (d, J = 5.2 Hz, 1H), 6.91-6.92 (d, J = 5.2 Hz, 1H), 6.73 (s, 2H), 4.24 (s, 2H), 3.85 (s, 2H), 3.55-3.58 (t, Ji = 5.6 Hz, J 2 = 6.0 Hz, 2H), 2.89 ( s, 2H), 2.10 (s, 6H).
实施例一百五 ^一  Example one hundred five ^ one
N-(4-(6，7-二氢噻吩 [3，2-C]吡啶 -5(4H)-基) -2，6-二甲基苯) -3- (4-氟苯基） 丙酰胺的制备 N-(4-(6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3-(4-fluorophenyl)propene Preparation of amide
Figure imgf000116_0002
Figure imgf000116_0002
3-(4-氟苯)丙酰氯 （化合物 151A) 3- (4-氟苯)丙酸 (3 g， 0.018 mol)溶于干燥的二氯甲烷，降至 0°C， 然后加入草酰氯 (1.85 ml, 0.02 mol)和一滴 DMF， 室温搅拌反应 3小时。反应结束， 直接加压浓縮， 得到的化合物 151A 直接用于下一步反应。 3-(4-fluorophenyl)propionyl chloride (compound 151A) 3-(4-Fluorophenyl)propionic acid (3 g, 0.018 mol) was dissolved in dry dichloromethane to 0 ° C, then oxalyl chloride (1.85 ml, 0.02 mol) and a drop of DMF were added, and the reaction was stirred at room temperature 3 hour. After completion of the reaction, the mixture was directly concentrated under pressure, and the obtained compound 151A was directly used for the next reaction.
N- (4-溴 -2， 6-二甲基苯） -3- (4-氟苯） 丙酰胺 （化合物 151B)  N-(4-Bromo-2,6-dimethylphenyl)-3-(4-fluorophenyl)propanamide (Compound 151B)
4-溴 -2, 6-二甲基苯胺（3.9 g， 0.02 mol)和三乙胺（5.45 g， 0.054 mol)溶于干燥的二氯甲 烷， 降至 0°C， 然后加入化合物 151A， 室温搅拌反应 1小时。 浓縮反应液， 所得固体用乙酸 乙酯洗涤， 得到化合物 151B ( 3.2 g， 51%收率）。  4-Bromo-2,6-dimethylaniline (3.9 g, 0.02 mol) and triethylamine (5.45 g, 0.054 mol) were dissolved in dry dichloromethane to 0 ° C, then compound 151A was added at room temperature The reaction was stirred for 1 hour. The reaction mixture was concentrated, and the obtained solid was washed with ethyl acetate to afford Compound 151B ( 3.2 g, 51% yield).
N-(4-(6，7-二氢噻吩 [3，2-C]吡啶 -5(4H)-基) -2,6-二甲基苯) -3- (4-氟苯基） 丙酰胺 （化合物N-(4-(6,7-Dihydrothiophene[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3-(4-fluorophenyl)propene Amide
151 ) 151)
本品由化合物 151B( 553 mg,1.58 mmol)和 4，5，6，7-四氢噻吩 [3，2-c]吡啶 (200mg，0.44 mmol) 按照化合物 120的制备方法合成， 氮气保护下 110°C反应 5小时得到产物 (170 mg，29%收率)。 MS: 369.3 (M+H+). 1H NMR (400 MHz, DMSO- d6) δ: 8.96 (s, 1H), 7.29 (m， 3H), 7.11(t, J= 8.8 Hz, 2H), 6.91 (d, J= 5.2 Hz, 1H)， 6.69 (s， 2H), 4.24 (s， 2H), 3.54 (m， 2H), 2.90(m, 4H)， 2.59 (m， 2H), 1.97 (s, 6H).  This product is synthesized from compound 151B ( 553 mg, 1.58 mmol) and 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine (200 mg, 0.44 mmol) according to the preparation method of compound 120, under nitrogen protection 110 The reaction was carried out at ° C for 5 hours to give the product (170 mg, 29% yield). MS: 369.3 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ: 8.96 (s, 1H), 7.29 (m, 3H), 7.11 (t, J = 8.8 Hz, 2H), 6.91 (d , J= 5.2 Hz, 1H), 6.69 (s, 2H), 4.24 (s, 2H), 3.54 (m, 2H), 2.90 (m, 4H), 2.59 (m, 2H), 1.97 (s, 6H) .
实施例一百五十二  Example one hundred fifty two
N- (4- ( 6 7-二氢噻吩 [3，2-c]-5(4H)-基） -2，6-二甲氧基苯基） -3-氟苯丙酰胺的制备
Figure imgf000117_0001
Preparation of N-(4-(6 7-dihydrothiophene[3,2-c]-5(4H)-yl)-2,6-dimethoxyphenyl)-3-fluorophenylpropanamide
Figure imgf000117_0001
3-氟苯丙酰氯 （化合物 152A)  3-fluorophenylpropionyl chloride (compound 152A)
将化合物 3-氟苯丙酸 （202 mg， 1.20 mmol) 溶于 5 mL无水二氯甲烷溶液中， 滴加 1滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯 （305 mg， 2.40 mmol )。 1分钟后滴加完 毕， 升至室温搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 152A, 未经纯化 直接用于下一步反应。  Dissolve the compound 3-fluorophenylpropionic acid (202 mg, 1.20 mmol) in 5 mL of anhydrous dichloromethane, add 1 drop of N,N-dimethylformamide dropwise, under nitrogen, drop at 0 °C Add oxalyl chloride (305 mg, 2.40 mmol). After completion of the dropwise addition for 1 minute, the reaction was stirred at room temperature for 1 hour, and dichloromethane and the residue of oxalyl chloride were evaporated to give crude compound 152A.
N- (4- ( 6,7-二氢噻吩 [3，2-c]-5(4H)-基） -2,6-二甲氧基苯基） -3-氟苯丙酰胺（化合物 152) 将化合物 4- ( 6,7-二氢噻吩 [3，2-c]-5(4H)-基） -2,6-二甲氧基苯胺 （235 mg， 0.91 mmol) 溶 于 5 mL无水二氯甲烷中， 加入三乙胺 （507 mg， 5.01 mmol), 0 °C下滴加化合物 152A的无 水二氯甲烷溶液（2 mL)。滴加完毕，氮气保护下室温搅拌反应 1小时，加水， 二氯甲烷萃取， 合并， 干燥， 经制备纯化得化合物 152 ( 103 mg， 28%收率）。 MS: 409.3 (M+H+). 1H NMR (400 MHz, CD3C1) δ: 7.09-7.28 (m, 2H), 6.70-7.08 (m, 2H), 6.53-6.94 (m,3H), 6.69 (s, 1H), 6.52 (s, 1H )， 4.28 (s,2H), 3.58-3.64 (m， 2H), 2.94-3.00 (m， 2H), 2.76-2.85 (m， 2H), 2.70-2.74 (m,2H), 2.09 (s， 6H). N-(4-(6,7-dihydrothiophene[3,2-c]-5(4H)-yl)-2,6-dimethoxyphenyl)-3-fluorophenylpropanamide (compound 152 The compound 4-(6,6-dihydrothiophene[3,2-c]-5(4H)-yl)-2,6-dimethoxyaniline (235 mg, 0.91 mmol) was dissolved in 5 mL To a solution of methylene chloride, triethylamine (507 mg, 5.01 mmol) was added dropwise. After completion of the dropwise addition, the reaction was stirred at room temperature under nitrogen for 1 hour, water was added, extracted with dichloromethane, combined, dried and purified to afford compound 152 (103 mg, 28% yield). MS: 409.3 (M+H + ). 1H NMR (400 MHz, CD3C1) δ: 7.09-7.28 (m, 2H), 6.70-7.08 (m, 2H), 6.53-6.94 (m,3H), 6.69 (s , 1H), 6.52 (s, 1H ), 4.28 (s, 2H), 3.58-3.64 (m, 2H), 2.94-3.00 (m, 2H), 2.76-2.85 (m, 2H), 2.70-2.74 (m, 2H), 2.09 (s, 6H).
实施例一百五十三  Example one hundred fifty three
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -2- (3,4-二甲氧基苯基） 乙酰 胺的制
Figure imgf000118_0001
N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3,4-dimethyl Oxyphenyl) acetamide
Figure imgf000118_0001
2-氟 -3-苯丙酰氯 （化合物 153A)  2-fluoro-3-phenylpropionyl chloride (compound 153A)
将化合物 2-氟苯丙酸 （3.00 g， 0.018 mol) 溶于 60 mL无水二氯甲烷溶液中， 滴加 1滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯 （4.57 g， 0.036 mol)。 15分钟后滴加完 毕， 升至室温搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 153A, 未经纯化 直接用于下一步反应。  The compound 2-fluorophenylpropionic acid (3.00 g, 0.018 mol) was dissolved in 60 mL of anhydrous dichloromethane, and 1 drop of N,N-dimethylformamide was added dropwise, and the solution was dropped at 0 °C under nitrogen. Add oxalyl chloride (4.57 g, 0.036 mol). After the completion of the dropwise addition for 15 minutes, the mixture was stirred at room temperature for 1 hour, and dichloromethane and the residue of oxalyl chloride were obtained to afford crude compound 153A.
N- (4-溴 -2,6-二甲基苯基） -2-氟 3-苯丙酰胺 （化合物 153B)  N-(4-Bromo-2,6-dimethylphenyl)-2-fluoro-3-phenylpropanamide (Compound 153B)
将化合物 4-溴 -2,6-二甲基苯胺 （3.60 g， 0.018 mol) 溶于 80 mL无水二氯甲烷中， 加入三 乙胺 （5.46 g， 0.054 mol), 0 °C下滴加化合物 153A的无水二氯甲烷溶液 （20 mL), 20分钟 后滴加完毕。 氮气保护下室温搅拌反应 2小时， 大量沉淀产生， 过滤， 用少量干燥的二氯甲 烷洗涤， 干燥得化合物 153B (3.33 g， 53%收率）。 MS: 350.2 (M+H+). The compound 4-bromo-2,6-dimethylaniline (3.60 g, 0.018 mol) was dissolved in 80 mL of anhydrous dichloromethane, triethylamine (5.46 g, 0.054 mol) was added, and the mixture was added dropwise at 0 °C. A solution of Compound 153A in anhydrous dichloromethane (20 mL) was applied dropwise over 20 min. The reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere, and a large amount of precipitated, which was filtered, washed with a little dry methylene chloride and dried to afford compound 153B (3.33 g, 53% yield). MS: 350.2 (M+H + ).
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -2- (3,4-二甲氧基苯基） 乙酰 胺 （化合物 153 )  N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(3,4-dimethyl Oxyphenyl) acetamide (compound 153)
本品由化合物 153B (553 mg, 1.58 mmol)和 4，5，6，7-四氢噻吩并 [3，2-c]卩比啶 (200 mg, 1.44 mmol)按照化合物 120的制备方法合成， 氮气保护下 120 °C搅拌 2小时得化合物 153， 为白 色固体 ( 18 mg, 3%收率)。 MS: 409.3 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.28-7.31 (m， 1H)， 7.20-7.24 (m， 1H)， 7.14-7.16 (m， 1H)， 7.04-7.13 (m， 2H), 6.84-6.86 (m， 1H), 6.70 (s， 2H), 6.54(s， 1H), 4.28 (s， 2H), 3.58-3.63 (m， 2H), 3.12-3.16 (t， Ji = 7.6 Hz, J2 = 7.2 Hz, 2H), 2.99 (s， 2H), 2.72-2.76 (m， Ji = 7.6 Hz, J2 = 7.2 Hz, 2H), 2.08 (s， 6H). This product was synthesized from compound 153B (553 mg, 1.58 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridinium (200 mg, 1.44 mmol) according to the preparation of compound 120. The compound 153 was obtained as a white solid (18 mg, 3% yield). MS: 409.3 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.28-7.31 (m, 1H), 7.20-7.24 (m, 1H), 7.14-7.16 (m, 1H), 7.04- 7.13 (m, 2H), 6.84-6.86 (m, 1H), 6.70 (s, 2H), 6.54(s, 1H), 4.28 (s, 2H), 3.58-3.63 (m, 2H), 3.12-3.16 ( t, Ji = 7.6 Hz, J 2 = 7.2 Hz, 2H), 2.99 (s, 2H), 2.72-2.76 (m, Ji = 7.6 Hz, J 2 = 7.2 Hz, 2H), 2.08 (s, 6H).
实施例一百五十四  Example one hundred fifty four
3- (4-氯苯基) -N- (4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 丙酰 胺的制备
Figure imgf000119_0001
3-(4-Chlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl Preparation of propionamide
Figure imgf000119_0001
3- (4-氯苯基） 丙酰氯 （化合物 154A)  3-(4-Chlorophenyl)propionyl chloride (Compound 154A)
将化合物对氟苯丙酸 （168 mg， 0.91 mmol) 溶于 10 mL无水二氯甲烷溶液中， 滴加 1滴 N，N-二甲基甲酰胺， 氮气保护下， 于 0 °C滴加草酰氯 （ 168 mg， 0.91 mmol )。 1分钟后滴加完 毕， 升至室温搅拌反应 1小时， 旋除二氯甲烷和剩余的草酰氯得粗品化合物 154A, 未经纯化 直接用于下一步反应。  The compound p-fluoropropionic acid (168 mg, 0.91 mmol) was dissolved in 10 mL of anhydrous dichloromethane, 1 drop of N,N-dimethylformamide was added dropwise, and the mixture was added at 0 °C under nitrogen. Oxalyl chloride (168 mg, 0.91 mmol). After completion of the dropwise addition for 1 minute, the reaction was stirred at room temperature for 1 hour, and dichloromethane and the residue of oxalyl chloride were evaporated to give crude compound 154A.
(4- ( 6,7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2,6-二甲基苯基）叔丁氧羰基酰胺 （化合 物 154B) (4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)tert-butoxycarbonylamide (Compound 154B)
氮气保护下，将三 (二亚苄基丙酮)二钯（0) (247 mg, 0.27 mmol)和 4，5-双 (二苯基膦) -9,9- 二甲基氧杂蒽（Xantphos, 181 mg, 0.38 mmol)溶于 20 mL 的甲苯溶液中搅拌 15分钟， 然后 向溶液中依次加入 4，5，6，7-四氢噻吩并 [3，2-c]吡啶 ( 528 mg, 3.79 mmol), 4-溴 -2,6-二甲基苯基 叔丁氧羰基胺（ 1.14 g， 1.58 mmol)和叔丁醇钾 （ 1.70 g， 15.2 mmol)。 反应液加热至 120 °〇搅 拌过夜。旋除溶剂，粗品经石油醚 /乙酸乙酯 =10: 1过柱纯化得其化合物 154B,为黄色固体（200 mg, 15%收率） 。 MS: 359.3 (M+H+).  Tris(dibenzylideneacetone)dipalladium(0) (247 mg, 0.27 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxene (Xantphos) under nitrogen protection , 181 mg, 0.38 mmol) was dissolved in 20 mL of toluene for 15 minutes, then 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (528 mg, 3.79) was added to the solution. Methyl) 4-bromo-2,6-dimethylphenyl tert-butoxycarbonylamine ( 1.14 g, 1.58 mmol) and potassium t-butoxide (1. 70 g, 15.2 mmol). The reaction solution was heated to 120 ° and stirred overnight. The solvent was evaporated and the crude was purified EtOAc EtOAcjjjjj MS: 359.3 (M+H+).
4- ( 6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基） -2,6-二甲基苯胺 （化合物 154C)  4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (Compound 154C)
将化合物 154B (200 mg, 0.56 mmol) 溶于 5 mL二氯甲烷溶液中， 0 °〇下滴加三氟乙酸 ( 192 mg, 1.68 mmol) 。 滴加完毕， 升至室温搅拌反应 1小时， 旋除二氯甲烷和剩余的三氟 乙酸。 加水， 用饱和氢氧化钠水溶液调节溶液至碱性， 二氯甲烷萃取， 合并， 干燥， 浓縮得 化合物 154C ( 144 mg， 100%收率） 。 MS: 259.2 (M+H+).  Compound 154B (200 mg, 0.56 mmol) was dissolved in 5 mL dichloromethane and then trifluoroacetic acid ( 192 mg, 1. After completion of the dropwise addition, the reaction was stirred at room temperature for 1 hour, and dichloromethane and the remaining trifluoroacetic acid were evaporated. Water was added, the solution was adjusted to basic with aq. EtOAc EtOAc. EtOAc (EtOAc) MS: 259.2 (M+H+).
3- (4-氯苯基) -N- (4- ( 6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 丙酰 胺 （化合物 154)  3-(4-Chlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl ) propionamide (compound 154)
将化合物 154C ( 144 mg, 0.56 mol)溶于 5 mL无水二氯甲烷中，加入三乙胺（227 mg, 2.24 mol), 0 °C下滴加化合物 154A的无水二氯甲烷溶液（2 mL)。 滴加完毕后， 氮气保护下室温 搅拌反应 1 小时。 加水， 二氯甲烷萃取， 合并， 干燥， 经制备分离纯化得化合物 154， 为白 色固体（ 18 mg, 8%收率）。 MS: 425.2 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.30 (s, 1H), 7.29 (s: 2H), 7.20-7.24 (m， 1H)， 7.14-7.17 (m， 1H), 7.06-7.08 (d, J= 8.4 Hz, 1H )， 6.84-6.87 (m，lH)， 6.69 (s， 2H), 6.50-6.52 (m， 1H), 4.28 (s， 2H), 3.58-3.61 (t， Ji = J2 = 5.6 Hz, 2H), 305-3.09 (t， Ji = 7.6 Hz, J2 = 7.2 Hz, 2H), 2.99-3.02 (m， 2H), 2.68-2.72 (t， Ji = 7.2 Hz, J2 = 7.6 Hz, 2H), 2.22-2.25 (t， Ji = J2 = 7.6 Hz, 1H)， 2.08 (s, 6H). Compound 154C (144 mg, 0.56 mol) was dissolved in 5 mL of anhydrous dichloromethane, triethylamine (227 mg, 2.24 mol) was added, and a solution of compound 154A in anhydrous dichloromethane was added dropwise at 0 °C (2 mL). After the dropwise addition was completed, the reaction was stirred at room temperature under nitrogen for 1 hour. Add water, dilute with dichloromethane, combine, dry, and purified to afford compound 154 as a white solid (18 mg, 8% yield). MS: 425.2 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.30 (s, 1H), 7.29 (s : 2H), 7.20-7.24 (m, 1H), 7.14-7.17 (m, 1H), 7.06-7.08 (d, J= 8.4 Hz, 1H ), 6.84-6.87 (m, lH), 6.69 (s, 2H), 6.50-6.52 (m, 1H), 4.28 (s, 2H), 3.58-3.61 (t, Ji = J 2 = 5.6 Hz, 2H), 305-3.09 (t, Ji = 7.6 Hz, J 2 = 7.2 Hz, 2H), 2.99-3.02 (m, 2H), 2.68-2.72 (t, Ji = 7.2 Hz, J 2 = 7.6 Hz, 2H), 2.22-2.25 (t, Ji = J 2 = 7.6 Hz, 1H), 2.08 (s, 6H).
实施例一百五十五  Example one hundred fifty five
3- (4-溴苯) -N- (4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 丙酰胺 的制备
Figure imgf000120_0001
3-(4-Bromobenzene)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl) Preparation of propionamide
Figure imgf000120_0001
5-氟 -1,3-二甲基 -2硝基苯 （化合物 155A)  5-fluoro-1,3-dimethyl-2nitrobenzene (compound 155A)
于 -15°C在氮气保护下往 1-氟 -3,5-二甲基苯 （100 g， 806 mmol) 中加入硝酸 （32 mL, 806 mmol), 然后与常温反应 3小时后， 将反应液倒入冰水中， 用乙酸乙酯萃取， 旋干， 用石油 醚重结晶得产品 （20 g， 15%收率）。  Nitric acid (32 mL, 806 mmol) was added to 1-fluoro-3,5-dimethylbenzene (100 g, 806 mmol) under nitrogen at -15 ° C, and then reacted with normal temperature for 3 hours. The solution was poured into ice water, extracted with EtOAc EtOAc (EtOAc)
5- (3,5-二甲基 -4-硝基苯基） -4，5，6，7-四氢噻吩并 [3，2-c]吡啶 （化合物 155B)  5-(3,5-Dimethyl-4-nitrophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Compound 155B)
将 4，5，6，7-四氢噻吩并 [3，2-c]口比啶 (0.7 mL, 5.9 mmol), 化合物 155A(1 g， 5.9 mmol)，碳酸 铯（7.7 g， 24 mmol)和 N，N-二甲基甲酰胺（30 mL)回流 24小时。然后萃取， 饱和食盐水洗， 旋干得粗品， 用石油醚 /乙酸乙酯 = 100/1纯化得产品 （400 mg，24%收率）。  4,5,6,7-Tetrahydrothieno[3,2-c]pyridinium (0.7 mL, 5.9 mmol), Compound 155A (1 g, 5.9 mmol), cesium carbonate (7.7 g, 24 mmol) It was refluxed with N,N-dimethylformamide (30 mL) for 24 hours. After extraction, the mixture was washed with EtOAc (EtOAc)EtOAc.
4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基） -2,6-二甲基苯胺 （化合物 155C)  4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (Compound 155C)
化合物 155B (400 mg, 1.39 mmol) 的甲醇 （15 mL) 溶液中加入钯碳 （20 mg)， 常温下 在氢气下反应 12小时， 过滤， 旋干得产品， 无需纯化直接用于下步反应中 （305 mg， 86%收 率）。 MS: 259 (M+H+)。  Palladium on carbon (20 mg) was added to a solution of compound 155B (400 mg, 1.39 mmol) in methanol (15 mL), and then reacted under hydrogen at ambient temperature for 12 hours, filtered, and dried to give the product, which was used in the next step without purification. (305 mg, 86% yield). MS: 259 (M+H+).
3- (4-溴苯) -N- (4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 丙酰胺 (化合物 155 )  3-(4-Bromobenzene)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl) Propionamide (compound 155)
往化合物 155C (305.5 mg, 1.16 mmol) 和三乙胺 (0.48 mL, 4.29 mmol) 的四氢呋喃 ( 15 mL) 溶液中滴加化合物 3-(4-溴苯基)丙酰氯 （300 mg， 1.16 mmol), 然后常温下反应 6小时， 旋干后用乙酸乙酯重结晶得产品 （100 mg, 18%收率）。 MS:469 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.98 (s， 1H), 7.48 (d， J = 8.4 Hz, 2H), 7.32 (d， J = 5.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 5.2 Hz, 1H)， 6.69 (s， 2H), 4.23 (s， 2H), 3.56-3.53 (m， 2H), 2.91-2.87 (m， 4H)， 2.62-2.58 (m， 2H), 1.97 (s， 6H). To a solution of the compound 155C (305.5 mg, 1.16 mmol) and triethylamine (0.48 mL, 4.29 mmol) in THF (15 mL) Then, it was reacted at room temperature for 6 hours, and after spinning, it was recrystallized from ethyl acetate to give a product (100 mg, 18% yield). MS: 469 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.98 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 5.2 Hz, 1H), 6.69 (s, 2H), 4.23 (s, 2H), 3.56-3.53 (m, 2H), 2.91-2.87 (m, 4H), 2.62-2.58 (m, 2H), 1.97 (s, 6H).
实施例一百五十六 N- (4- (6，7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2，6-二甲基苯基） -对甲基苯丙酰胺的 制备 Example one hundred fifty six Preparation of N-(4-(6,7-dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-p-methylphenylpropanamide
Figure imgf000121_0001
Figure imgf000121_0001
对甲基苯丙酰氯 （化合物 156A)  p-Methylphenylpropionyl chloride (Compound 156A)
将对甲基苯丙酸 （4 g， 24 mmol) 的二氯亚砜 （15 mL) 溶液回流 3小时， 旋干得产品， 直接用于下步反应 （4.45 g， 100%收率）。  A solution of p-methylphenylpropionic acid (4 g, 24 mmol) in chlorosulfoxide (15 mL) was refluxed for 3 hrs and then evaporated to give the product, which was used directly for the next step (4.45 g, 100% yield).
N- (4-溴 -2,6-二甲基苯） -对甲基苯丙酰胺 （化合物 156B)  N-(4-bromo-2,6-dimethylphenyl)-p-methylphenylpropanamide (compound 156B)
将 4-溴 -2,6-二甲基苯胺（4.87 g， 24 mmol)和三乙胺（10.2 mL， 72 mmol)的四氢呋喃（30 mL) 溶液在常温下搅拌 30分钟， 然后滴入化合物 156A (4.45 g， 24 mmol)。 反应 6小时后， 反应液用水洗， 旋干， 用乙酸乙酯重结晶， 过滤得产品 （6.4 g， 76%收率）。 MS: 346 (M+H+)。 A solution of 4-bromo-2,6-dimethylaniline (4.87 g, 24 mmol) and triethylamine (10.2 mL, 72 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 30 min, then 156A (4.45 g, 24 mmol). After reacting for 6 hours, the reaction mixture was washed with EtOAc EtOAc m. MS: 346 (M+H + ).
N- (4- (6,7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2,6-二甲基苯基） -对甲基苯丙酰胺（化 合物 156) N-(4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-p-methylphenylpropanamide (compound) 156)
本品由化合物 156B (200 mg， 0.58 mmol)和 4，5，6，7-四氢噻吩并 [3，2-c]卩比啶 (0.07 mL, 0.58 mmol)按照化合物 120的制备方法合成，氮气保护下 120°C下反应 6小时得产物（ 100 mg， 43 % 收率）。 MS: 405 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 7.29-7.18 (m， 2Η), 7.15-7.13 (m， 2H), 7.07-7.00 (m, 1H), 6.87-6.84 (m, 1H), 6.69 (s, 2H), 6.49 (s, 1H), 4.32- 4.28 (m, 2H), 3.64-3.58 (m, 2H), 3.09-3.05 (m, 2H), 3.00-2.97 (m, 2H), 2.74-2.70 (m, 2H), 2.35-2.30 (m, 3H), 2.14-2.09 (m, 6H).  This product is synthesized from compound 156B (200 mg, 0.58 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridinium (0.07 mL, 0.58 mmol) according to the preparation of compound 120. The product was obtained by reacting at 120 ° C for 6 hours under nitrogen atmosphere (100 mg, 43% yield). MS: 405 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 7.29-7.18 (m, 2 Η), 7.15-7.13 (m, 2H), 7.07-7.00 (m, 1H), 6.87- 6.84 (m, 1H), 6.69 (s, 2H), 6.49 (s, 1H), 4.32- 4.28 (m, 2H), 3.64-3.58 (m, 2H), 3.09-3.05 (m, 2H), 3.00- 2.97 (m, 2H), 2.74-2.70 (m, 2H), 2.35-2.30 (m, 3H), 2.14-2.09 (m, 6H).
实施例一百五十七  Example one hundred fifty seven
N- (4- (6，7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2,6-二甲基苯基） -对甲氧基苯丙酰胺 的制备 N-(4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-p-methoxyphenylpropanamide preparation
Figure imgf000121_0002
Figure imgf000121_0002
对甲氧基苯丙酰氯 （化合物 157A)  P-methoxyphenylpropionyl chloride (Compound 157A)
将对甲基苯丙酸 （5 g， 27.7 mmol) 的二氯亚砜 （15 mL) 溶液回流 3小时， 旋干得产品， 直接用于下步反应 （5.51 g， 100%收率）。 N- (4-溴 -2，6-二甲基苯） -对甲氧基苯丙酰胺 （化合物 157B) A solution of p-methylphenylpropionic acid (5 g, 27.7 mmol) in dichloromethane (15 mL) was refluxed for 3 h and then evaporated to dryness. N-(4-bromo-2,6-dimethylphenyl)-p-methoxyphenylpropanamide (compound 157B)
将 4-溴 -2,6-二甲基苯胺（5.55 g， 27.7 mmol)和三乙胺（ 11.6 mL， 83.2 mmol) 的四氢呋喃 ( 30 mL)溶液在常温下搅拌 30分钟， 然后滴入化合物 157A ( 5.51 g， 27.7 mmol)。 反应 6小 时后， 反应液用水洗， 旋干， 用乙酸乙酯重结晶， 过滤得产品 （4.4 g， 44%收率）。 MS: 362 (M+H+)。  A solution of 4-bromo-2,6-dimethylaniline (5.55 g, 27.7 mmol) and triethylamine (1. 6 mL, 83.2 mmol) in tetrahydrofuran (30 mL) was stirred at ambient temperature for 30 min, then 157A (5.51 g, 27.7 mmol). After reacting for 6 hours, the reaction mixture was washed with EtOAc EtOAc. MS: 362 (M+H+).
N- (4- ( 6,7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2,6-二甲基苯基） -对甲氧基苯丙酰胺 (化合物 157) N-(4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-p-methoxyphenylpropanamide ( Compound 157)
本品由化合物 157B (200 mg, 0.55 mmol)和 4，5，6，7-四氢噻吩并 [3，2-c]卩比啶 ( 0.07 mL, 0.55 mmol)按照化合物 120的制备方法合成， 氮气保护下 120°C下反应 6小时， 然后制备纯化得 产物 ( 100 mg, 43 %收率）。 MS: 421 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 7.28-7.03 (m， 4H)， 6.86-6.66 (m， 3H), 6.47-6.32 (m， 1H), 6.23-6.14 (m， 1H), 3.81-3.77 (m， 5H)， 3.04 (s， 3H), 2.88-2.72 (m， 2H), 2.12-1.85 (m， 6H)， 1.61 (s， 3H).  This product was synthesized from compound 157B (200 mg, 0.55 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridinium (0.07 mL, 0.55 mmol) according to the preparation of compound 120. The reaction was carried out at 120 ° C for 6 hours under a nitrogen atmosphere, and then the purified product was obtained (100 mg, 43% yield). MS: 421 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 7.28-7.03 (m, 4H), 6.86-6.66 (m, 3H), 6.47-6.32 (m, 1H), 6.23- 6.14 (m, 1H), 3.81-3.77 (m, 5H), 3.04 (s, 3H), 2.88-2.72 (m, 2H), 2.12-1.85 (m, 6H), 1.61 (s, 3H).
实施例一百五十八  Example one hundred fifty eight
N- (4- ( 6，7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基） -2,6-二甲基苯基） -对三氟甲基苯丙酰 胺的制备  N-(4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-p-trifluoromethylphenylpropanamide Preparation
Figure imgf000122_0001
Figure imgf000122_0001
对三氟甲基苯丙酰氯 （化合物 158A)  P-trifluoromethylphenylpropionyl chloride (compound 158A)
将对三氟甲基苯丙酸 （4 g， 18 mmol) 的二氯亚砜 （10 mL) 溶液回流 3小时， 旋干得产 品， 直接用于下步反应 （4.33 g， 100%收率）。  A solution of p-trifluoromethyl phenylpropionic acid (4 g, 18 mmol) in dichloromethane (10 mL) was refluxed for 3 h and then dried to give the product directly to the next step (4.33 g, 100% yield) .
N- (4-溴 -2,6-二甲基苯） -对三氟甲基苯丙酰胺 （化合物 158B)  N-(4-Bromo-2,6-dimethylphenyl)-p-trifluoromethylphenylpropanamide (Compound 158B)
将 4-溴 -2,6-二甲基苯胺（3.67 g， 18 mmol)和三乙胺（7.65 mL, 54 mmol)的四氢呋喃（30 mL) 溶液在常温下搅拌 30分钟， 然后滴入化合物 158A (4.33 g， 18 mmol)。 反应 6小时后， 反应液用水洗， 旋干， 用乙酸乙酯重结晶， 过滤得产品 （4 g，55%收率）。  A solution of 4-bromo-2,6-dimethylaniline (3.67 g, 18 mmol) and triethylamine (7.65 mL, 54 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 30 min, then 158A (4.33 g, 18 mmol). After reacting for 6 hours, the reaction mixture was washed with water, dried, evaporated, evaporated
N- (4- ( 6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基） -2,6-二甲基苯基） -对三氟甲基苯丙酰 胺 （化合物 158 )  N-(4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-p-trifluoromethylphenylpropanamide (compound 158)
本品由化合物 158B ( 300 mg， 0.75 mmol)和 4，5，6，7-四氢噻吩并 [3，2-c]吡啶（0.088 mL， 0.75 mmol)按照化合物 120的制备方法合成，氮气保护下 120°C下反应 6小时得产物（ 100 mg, 29 % 收率）。 MS: 405 (M+H+). MS: 459 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 7.59-7.57,7.43-7.41 (m， 3H), 7.51-7.49, 7.28-7.25 (m， 1H), 7.17-7.14 (m， 1H), 6.87-6.84 (m， 1H)， 6.69 (s, 2H), 6.53-6.52 (m， 1H), 4.32- 4.28 (m， 2H), 3.66-3.58 (m， 2H), 3.18-2.99 (m， 4H)， 2.76-2.72,2.29-2.26 (m， 2H), 2.09-2.05 (m， 6H). This product is synthesized from compound 158B (300 mg, 0.75 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.088 mL, 0.75 mmol) according to the preparation of compound 120. The product was obtained by reacting at 120 ° C for 6 hours (100 mg, 29 % Yield). MS: 405 (M+H+). MS: 459 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 7.59-7.57, 7.43-7.41 (m, 3H), 7.51-7.49, 7.28-7.25 (m, 1H), 7.17-7.14 (m, 1H), 6.87-6.84 (m, 1H), 6.69 (s, 2H), 6.53-6.52 (m, 1H), 4.32- 4.28 (m, 2H), 3.66 -3.58 (m, 2H), 3.18-2.99 (m, 4H), 2.76-2.72, 2.29-2.26 (m, 2H), 2.09-2.05 (m, 6H).
实施例一百五十九  Example one hundred fifty nine
3-(2，4-二氟苯基) -N- (4- ( 6，7-二氢噻吩并[3，2-0 |吡啶-5 (4H) -基) -2,6-二甲基苯基) 丙 酰胺的制备  3-(2,4-difluorophenyl)-N-(4-(6,7-dihydrothieno[3,2-0]pyridin-5(4H)-yl)-2,6-dimethyl Preparation of phenyl amide
Figure imgf000123_0001
Figure imgf000123_0001
3-(2，4-二氟苯基)丙酰氯 （化合物 159A)  3-(2,4-difluorophenyl)propanoyl chloride (Compound 159A)
往 3-(2，4-二氟苯基)丙酸 （l g， 5.4 mmol) 的二氯甲烷 （20 mL)溶液中加入草酰氯 （1.53 mL, 16 mmol),然后滴加一滴 N，N-二甲基甲酰胺， 反应液于常温下反应 3小时， 旋干得产品， 直接用于下步反应 （ 1.09 g， 100%收率）。  Add oxalyl chloride (1.53 mL, 16 mmol) to a solution of 3-(2,4-difluorophenyl)propanoic acid (1 g, 5.4 mmol) in dichloromethane (20 mL). Dimethylformamide, the reaction solution was reacted at room temperature for 3 hours, and the product was spun dry and used directly in the next step ( 1.09 g, 100% yield).
N- (4-溴 -2,6-二甲基苯） -3-(2，4-二氟苯基)丙酰胺 （化合物 159B)  N-(4-Bromo-2,6-dimethylphenyl)-3-(2,4-difluorophenyl)propanamide (Compound 159B)
将 4-溴 -2,6-二甲基苯胺 ( 1.1 g, 5.3 mmol)和三乙胺 (2.2 mL, 16 mmol) 的四氢呋喃 ( 10 mL) 溶液在常温下搅拌 30分钟， 然后滴入化合物 159A ( 1.09 g， 5.3 mmol)。 反应 6小时后， 反应液用水洗， 旋干， 用乙酸乙酯重结晶， 过滤得产品 （l g，51%收率）。 MS: 368 (M+H+)。 A solution of 4-bromo-2,6-dimethylaniline (1.1 g, 5.3 mmol) and triethylamine (2.2 mL, 16 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 30 min, then 159A ( 1.09 g, 5.3 mmol). After 6 hours of reaction, the reaction mixture was washed with EtOAc EtOAc m. MS: 368 (M+H + ).
3-(2，4-二氟苯基) -N- (4- ( 6，7-二氢噻吩并[3，2-0 |吡啶-5 (4H) -基) -2,6-二甲基苯基) 丙 酰胺 （化合物 159)  3-(2,4-difluorophenyl)-N-(4-(6,7-dihydrothieno[3,2-0]pyridin-5(4H)-yl)-2,6-dimethyl Phenyl phenyl) propionamide (compound 159)
本品由化合物 159B (300 mg, 0.82 mmol)和 4，5，6，7-四氢噻吩并 [3，2-c]卩比啶 ( 113 mg, 0.81 mmol)按照化合物 120的制备方法合成，氮气保护下 120°C下反应 6小时得产物（30 mg， 9 % 收率）。 MS: 427 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.01 (s, 1H), 7.38-7.32 (m， 2H), 7.23-7.17 (m， 1H), 7.05-7.01 (m， 1H), 6.91 (d, J= 5.6， 1H), 6.69 (s, 2H), 4.22 (s, 2H), 3.56-3.53 (m， 2H), 2.93-2.89 (m， 4H)， 2.62-2.58 (m， 2H), 2.02-1.97 (m， 6H). This product was synthesized from compound 159B (300 mg, 0.82 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridinium (113 mg, 0.81 mmol) according to the preparation of compound 120. The product was obtained by reacting at 120 ° C for 6 hours under nitrogen atmosphere (30 mg, 9% yield). MS: 427 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.01 (s, 1H), 7.38-7.32 (m, 2H), 7.23-7.17 (m, 1H), 7.05-7.01 (m, 1H), 6.91 (d, J= 5.6, 1H), 6.69 (s, 2H), 4.22 (s, 2H), 3.56-3.53 (m, 2H), 2.93-2.89 (m, 4H), 2.62 -2.58 (m, 2H), 2.02-1.97 (m, 6H).
实施例一百六十  Example one hundred and sixty
3- (3，4-二氟苯基） -N- (4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 丙酰胺的制备
Figure imgf000124_0001
3-(3,4-Difluorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethyl Preparation of phenyl amide
Figure imgf000124_0001
3，4-二氟苯丙酰氯 （化合物 160A)  3,4-difluorophenylpropionyl chloride (Compound 160A)
往 3,4-二氟苯丙酸（4 g， 21.5 mmol), 草酰氯（6.13 mL， 64.5 mmol)的二氯甲烷（20 mL) 溶液中滴加一滴 N，N-二甲基甲酰胺，然后常温下反应 3小时，旋干后直接用于下步反应（6.34 g， 100%收率）。  To a solution of 3,4-difluorophenylpropionic acid (4 g, 21.5 mmol), oxalyl chloride (6.13 mL, 64.5 mmol) in dichloromethane (20 mL) Then, the reaction was carried out at normal temperature for 3 hours, and after spin-drying, it was directly used for the next step (6.34 g, 100% yield).
N- (4-溴 -2,6-二甲基苯） -3- (3,4-二氟苯基） 丙酰胺 （化合物 160B)  N-(4-Bromo-2,6-dimethylphenyl)-3-(3,4-difluorophenyl)propanamide (Compound 160B)
将 4-溴 -2,6-二甲基苯胺（6.3 g， 32 mmol)和三乙胺（ 13.1 mL， 96 mmol) 的四氢呋喃 （30 mL) 溶液在常温下搅拌 30分钟， 然后滴入化合物 160A (6.43 g， 32 mmol)。 反应 6小时后， 反应液用水洗， 旋干， 用乙酸乙酯重结晶， 过滤得产品 （6 g，52%收率）。  A solution of 4-bromo-2,6-dimethylaniline (6.3 g, 32 mmol) and triethylamine ( 13.1 mL, 96 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 30 min, then the compound 160A (6.43 g, 32 mmol). After 6 hours of reaction, the reaction mixture was washed with EtOAc EtOAc m.
3- (3,4-二氟苯基） -N- (4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 丙酰胺 （化合物 160)  3-(3,4-Difluorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethyl Phenyl phenyl) propionamide (compound 160)
本品由化合物 160B(300 mg， 0.82 mmol)和 4，5，6，7-四氢噻吩并 [3，2-c]吡啶（0.096 mL， 0.82 mmol)按照化合物 120的制备方法合成，氮气保护下 120°C下反应 6小时得产物（ 100 mg， 29 % 收率）。 MS: 427 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.29-7.09 (m， 4H)， 7.02-6.84 (m， 1H)， 6.70 (s, 1H), 6.58-6.51 (m， 1H), 4.34- 4.29 (m， 1H), 3.66-3.58 (m， 1H), 3.08-2.97 (m， 3H), 2.92-2.66 (m， 3H), 2.11 (s， 1H), 2.09 (s， 3H), 2.06-2.03 (m， 1H), 1.60 (s， 6H). This product is synthesized from compound 160B (300 mg, 0.82 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.096 mL, 0.82 mmol) according to the preparation of compound 120. The reaction was carried out at 120 ° C for 6 hours to give the product (100 mg, 29% yield). MS: 427 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.29-7.09 (m, 4H), 7.02-6.84 (m, 1H), 6.70 (s, 1H), 6.58-6.51 ( m, 1H), 4.34- 4.29 (m, 1H), 3.66-3.58 (m, 1H), 3.08-2.97 (m, 3H), 2.92-2.66 (m, 3H), 2.11 (s, 1H), 2.09 ( s, 3H), 2.06-2.03 (m, 1H), 1.60 (s, 6H).
实施例一百六 ^一  Example one hundred six ^ one
3- (2，4-二氯苯基) -N- (4- (6，7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -丙酰胺的制备  3-(2,4-Dichlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethyl Preparation of phenyl)-propionamide
Figure imgf000124_0002
Figure imgf000124_0002
(4- (6,7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2， 6-二甲基苯基） 甲酸叔丁酯 （化合物 161A) (4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)carboxylic acid tert-butyl ester (Compound 161A)
本品由 4-溴 -2， 6-二甲基苯基） 甲酸叔丁酯 （l g， 3.3 mmol)禾卩 4，5，6，7-四氢噻吩并 [3，2-c] 吡啶（563 mg， 3.3 mmol)按照化合物 120的制备方法合成， 氮气保护下 120°C下反应 8小时， 纯化得产品 （150 mg， 13%收率）。 4- ( 6，7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基） -2， 6-二甲基苯胺 （化合物 161B ) 化合物 161A ( 150 mg， 0.42 mmol) 和三氟乙酸 （5 mL) 溶于二氯甲烷 （5 mL) 中， 于This product consists of tert-butyl 4-bromo-2,6-dimethylphenyl)carboxylate (lg, 3.3 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine ( 563 mg, 3.3 mmol) was synthesized according to the preparation method of compound 120, and the product was purified by the reaction under nitrogen for 12 hours at 120 ° C (150 mg, 13% yield). 4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (Compound 161B) Compound 161A (150 mg, 0.42 mmol) Trifluoroacetic acid (5 mL) dissolved in dichloromethane (5 mL)
40°C下反应 2小时。 旋干， 水洗， 乙酸乙酯萃取， 饱和碳酸钠溶液洗， 旋干得产品 （lOO mg,The reaction was carried out at 40 ° C for 2 hours. Spin dry, wash, ethyl acetate extraction, wash with saturated sodium carbonate solution, spin dry to obtain product (100 mg,
93%收率）。 MS: 258 (M+H+)。 93% yield). MS: 258 (M+H+).
3- (2,4-二氯苯基) -N- (4- ( 6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) 3-(2,4-Dichlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethyl Phenylphenyl)
-丙酰胺 （化合物 161 ) -propionamide (compound 161)
化合物 161B ( 50 mg, 0.19 mmol) 和三乙胺 （0.08 mL， 0.58 mmol) 的四氢呋喃 （10 mL) 溶液在常温下搅拌 10分钟， 然后加入化合物 161 (46 mg，0.19 mmol)。 常温继续反应 8小时 制备得产物（20 mg, 22%收率）。 MS: 459 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 9.03 (s, 1H): 7.61 (d, J= 1.6 Hz, 1H), 7.42-7.39 (m， 2H), 7.33 (d, J= 5.2 Hz, 1H), 6.91 (d, J= 5.6， 1H), 6.71 (s， 2H), 4.23 (s， 2H), 3.56-3.54 (m， 2H), 3.02-2.98 (m， 2H), 2.89 (s， 2H), 2.64-2.61 (m， 2H), 2.04-1.99 (m， 6H). A solution of the compound 161B (50 mg, 0.19 mmol) and triethylamine (0.08 mL, 0.58 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 10 min, then compound 161 (46 mg, 0.19 mmol). The product was prepared by continuing the reaction at room temperature for 8 hours (20 mg, 22% yield). MS: 459 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.03 (s, 1H) : 7.61 (d, J = 1.6 Hz, 1H), 7.42-7.39 (m, 2H), 7.33 (d, J = 5.2 Hz, 1H), 6.91 (d, J= 5.6, 1H), 6.71 (s, 2H), 4.23 (s, 2H), 3.56-3.54 (m, 2H), 3.02-2.98 ( m, 2H), 2.89 (s, 2H), 2.64-2.61 (m, 2H), 2.04-1.99 (m, 6H).
实施例一百六十二  Example one hundred and sixty two
3- ( 3，5-二氯苯基） -N- (4- ( 6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -丙酰胺的制备
Figure imgf000125_0001
3-(3,5-Dichlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethyl Preparation of phenyl)-propionamide
Figure imgf000125_0001
3- ( 3,5-二氯苯基） 丙酰氯 （化合物 162A)  3-(3,5-Dichlorophenyl)propionyl chloride (Compound 162A)
将 3- ( 3,5-二氯苯基） 丙酸 （42 mg， 0.19 mmol), 草酰氯 （0.053 mL， 0.58 mmol) 溶于二 氯甲烷 （10 mL)， 然后加入一滴 N，N-二甲基甲酰胺， 常温反应 3小时后旋干得产品 （46 mg， 100%收率）。  3-( 3,5-Dichlorophenyl)propionic acid (42 mg, 0.19 mmol), oxalyl chloride (0.053 mL, 0.58 mmol) dissolved in dichloromethane (10 mL), then a drop of N,N- Methylformamide was reacted at room temperature for 3 hours and then dried to give the product (46 mg, 100% yield).
(4- ( 6,7-二氢噻吩并 [3，2-C]吡啶 -5 (4H) -基） -2， 6-二甲基苯基） 甲酸叔丁酯 （化合物 162B) (4-(6,7-Dihydrothieno[3,2- C ]pyridine-5(4H)-yl)-2,6-dimethylphenyl)carboxylic acid tert-butyl ester (Compound 162B)
将 4-溴 -2， 6-二甲基苯基）甲酸叔丁酯（1 g， 3.3 mmol), 4，5，6，7-四氢噻吩并 [3，2-c]吡啶（563 mg, 3.3 mmol) , 三 (；二亚苄基丙酮)二钯 (328 mg, 0.47 mmol), 2-二环己基磷 -2，4，6-三异丙基联苯 (239 mg， 0.5 mmol)，叔丁醇钾 （747 mg， 6.6 mmol) 和甲苯 （20 mL) 于 120°C下反应 8小时。 反应液用石油醚 /乙酸乙酯 = 20/1过柱纯化得产品 （150 mg， 13%收率）。  tert-Butyl 4-bromo-2,6-dimethylphenyl)carboxylate (1 g, 3.3 mmol), 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (563 mg , 3.3 mmol), tris(;dibenzylideneacetone)dipalladium (328 mg, 0.47 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (239 mg, 0.5 mmol) Potassium tert-butoxide (747 mg, 6.6 mmol) and toluene (20 mL) were reacted at 120 ° C for 8 hours. The reaction mixture was purified using petroleum ether / ethyl acetate = 20/1 to afford product (150 mg, 13% yield).
4- ( 6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基） -2， 6-二甲基苯胺 （化合物 162C ) 化合物 162B ( 150 mg, 0.42 mmol) 和三氟乙酸 （5 mL) 溶于二氯甲烷 （5 mL) 中， 于 40°C下反应 2小时。 旋干， 水洗， 乙酸乙酯萃取， 饱和碳酸钠溶液洗， 旋干得产品 （lOO mg, 93%收率）。 MS: 258 (M+H+)。 4-(6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (Compound 162C) Compound 162B (150 mg, 0.42 mmol) Trifluoroacetic acid (5 mL) dissolved in dichloromethane (5 mL) The reaction was carried out at 40 ° C for 2 hours. It was spin-dried, washed with water, extracted with ethyl acetate, washed with saturated sodium carbonate solution and dried to give product (100 mg, 93% yield). MS: 258 (M+H+).
3- (3,5-二氯苯基） -N- (4- (6,7-二氢噻吩并 [3，2-c]吡啶 -5 (4H) -基) -2,6-二甲基苯基) -丙酰胺 （化合物 162)  3-(3,5-Dichlorophenyl)-N-(4-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2,6-dimethyl Phenyl)-propionamide (compound 162)
化合物 162C (50 mg, 0.19 mmol) 和三乙胺 （0.08 mL， 0.58 mmol) 的四氢呋喃 （10 mL) 溶液在常温下搅拌 10分钟， 加入化合物 3-(3，5-二氯苯基)丙酰氯 （46 mg， 0.19 mmol)。 常温 继续反应 8小时， 制备得产物 （20 mg, 22%收率）。 MS: 459 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.99 (s， 1H), 7.45-7.44 (m， 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.32 (d， J = 5.2 Hz, 2H), 6.91 (d, J= 5.2, 1H), 6.70 (s, 2H), 4.23 (s, 2H), 3.56-3.53 (m， 2H), 2.95-2.87 (m， 4H)， 2.65-2.62 (m， 2H), 2.01-1.96 (m, 6H). Compound 162C (50 mg, 0.19 mmol) and triethylamine (0.08 mL, 0.58 mmol) in tetrahydrofuran (10 mL) were stirred at room temperature for 10 min, and the compound 3-(3,5-dichlorophenyl)propanoyl chloride was added. (46 mg, 0.19 mmol). The reaction was continued for 8 hours at room temperature to give the product (20 mg, 22% yield). MS: 459 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 8.99 (s, 1H), 7.45-7.44 (m, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 5.2 Hz, 2H), 6.91 (d, J= 5.2, 1H), 6.70 (s, 2H), 4.23 (s, 2H), 3.56-3.53 (m, 2H), 2.95-2.87 ( m, 4H), 2.65-2.62 (m, 2H), 2.01-1.96 (m, 6H).
实施例一百六十三  Example one hundred and sixty three
N-(4-(3，4-二氢吡咯并 l，2-a] 吡嗪 -2(1H)-基) -2,6-二甲基 )-3，3-二甲基丁酰胺的制备
Figure imgf000126_0001
N-(4-(3,4-dihydropyrrolo 1,2-a)pyrazine-2(1H)-yl)-2,6-dimethyl)-3,3-dimethylbutanamide preparation
Figure imgf000126_0001
( 1H-吡咯 -1- 基） 乙胺 (化合物 163A)  (1H-pyrrole-1-yl)ethylamine (compound 163A)
1H-吡咯 （2.09 mL, 30 mmol), 氢氧化钠 （6.0 g， 150 mmol)及 TBAS (0.51 g， 1.5 mmol)加入 到乙腈（30 mL) 中， 室温搅拌 30 分钟， 加入 2-氯乙胺盐酸盐 （4.18 g， 36 mmol), 升温至回 流反应 24 小时， 加入水 （100 mL), 乙酸乙酯萃取 （100 mLx3), 无水硫酸钠干燥， 减压旋 干， 二氯甲浣 /甲醇纯化得到产物 （2.66 g， 产率 81%)。  1H-pyrrole (2.09 mL, 30 mmol), sodium hydroxide (6.0 g, 150 mmol) and TBAS (0.51 g, 1.5 mmol) were added to acetonitrile (30 mL), stirred at room temperature for 30 min, then 2-chloroethylamine Hydrochloride (4.18 g, 36 mmol), warmed to reflux for 24 h, added water (100 mL), ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate. Purification by methanol gave the product (2.66 g, yield 81%).
1,2,3,4 - 四氢吡咯并 [l，2-a]吡嗪 (化合物 163B)  1,2,3,4 -tetrahydropyrrolo[l,2-a]pyrazine (Compound 163B)
化合物 163A (2.1 g， 19.1 mmol) 及 37% 的甲醛溶液 （0.53 mL, 19.1 mmol) 加入到乙醇 (30 ml) 中， 滴加三氟乙酸 （1.2 ml), 升温至 50 °C反应 15 分钟， 冷却到 25 °C在反应 4小时， 减压旋干， 二氯甲浣 /甲醇纯化得到产物 （932 mg， 产率 40%)。  Compound 163A (2.1 g, 19.1 mmol) and 37% formaldehyde solution (0.53 mL, 19.1 mmol) were added to ethanol (30 ml), trifluoroacetic acid (1.2 ml) was added dropwise, and the mixture was warmed to 50 ° C for 15 minutes. The mixture was cooled to 25 ° C for 4 hours, dried under reduced pressure, and purified with methylene chloride/methanol to afford product (932 mg, yield 40%).
N-(4-(3，4-二氢吡咯并 [l，2-a] 吡嗪 -2(1H)-基) -2,6-二甲基 )-3，3-二甲基丁酰胺 （化合物 163 ) 本品由化合物 163B (430 mg, 3.53 mmol)禾 B N- (4-溴代 -2,6-二甲基苯基） -3-甲基丁酰胺 (1.05 g， 3.53 mmol) 按照化合物 120的制备方法合成，氮气保护下 120°C反应 4小时得目标产 物 （200 mg， 产率 34% ). MS: 338 (M-H+)。 1腿 MR (CDC13， 400 MHz): δ 6.70 (s， 2H)， 6.59-6.91 (m， 1H)， 6.54 (s， 1H), 6.17-9.19 (m， 1H), 5.94-5.96 (m， 1H), 4.39 (s， 2H), 3.62 (t， J = 4.2 Hz, 2H), 3.62 (t, J= 4.2 Hz, 2H), 2.28 (s， 2H), 2.20 (s， 6H)， 1.14 (s， 9H). 实施例一百六十四 N-(4-(3,4-dihydropyrrolo[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethyl)-3,3-dimethylbutanamide (Compound 163) This product consists of Compound 163B (430 mg, 3.53 mmol) and B N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide (1.05 g, 3.53 mmol) The product was synthesized according to the preparation method of Compound 120, and reacted at 120 ° C for 4 hours under nitrogen atmosphere to give the objective product (200 mg, yield 34%). MS: 338 (M-H+). 1 leg MR (CDC1 3 , 400 MHz): δ 6.70 (s, 2H), 6.59-6.91 (m, 1H), 6.54 (s, 1H), 6.17-9.19 (m, 1H), 5.94-5.96 (m, 1H), 4.39 (s, 2H), 3.62 (t, J = 4.2 Hz, 2H), 3.62 (t, J = 4.2 Hz, 2H), 2.28 (s, 2H), 2.20 (s, 6H), 1.14 ( s, 9H). Example one hundred sixty four
N- (2-氯— (4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-6- (三氟甲基） 苯基) -3,3-二甲基丁酰胺的 制备  N-(2-Chloro-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-6-(trifluoromethyl)phenyl)-3,3- Preparation of dimethylbutyramide
Figure imgf000127_0001
Figure imgf000127_0001
4-溴 -2-氯 -6- (三氟甲基） 苯胺 （化合物 164A)  4-bromo-2-chloro-6-(trifluoromethyl)aniline (compound 164A)
0 °C和氮气的保护下， 在 4-溴 -2- (三氟甲基） 苯胺 (3 g， 12.5 mmol)的乙腈溶液中， 加入 1-氯 -1氢 -吡咯 -2,5-二酮 (1.67 g， 12.5 mmol), 将反应液升至 75°C搅拌 5小时后， 硫代硫酸钠 终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 过柱得化合物 164A (3.2 g，94% 收率).  Add 1-chloro-1 -hydrogen-pyrrole-2,5-di in 4-bromo-2-(trifluoromethyl)aniline (3 g, 12.5 mmol) in acetonitrile at 0 ° C under nitrogen. Ketone (1.67 g, 12.5 mmol), the reaction mixture was stirred at 75 ° C for 5 hours, then the solution was quenched with sodium thiosulfate, extracted with ethyl acetate, filtered, dried, and dried to give compound 164A (3.2 g, 94 % yield).
N- (4-溴 -2-氯 -6- (三氟甲基） 苯基） -3,3-二甲基丁酰胺 （化合物 164B)  N-(4-Bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (Compound 164B)
将 4-溴 -2-氯 -6- (三氟甲基）苯胺 (3.0 g， 10.9 mmol), 3,3-二甲基丁酰氯 (2.2 ml, 16.4 mmol) 和碳酸钾 (12 g， 87.7 mmol)的四氢呋喃溶液回流搅拌 24小时后， 过滤， 旋干， 过柱得到产物。 (1.7 g, 42% 收率) . MS: 372 (M+H+).  4-Bromo-2-chloro-6-(trifluoromethyl)aniline (3.0 g, 10.9 mmol), 3,3-dimethylbutyryl chloride (2.2 ml, 16.4 mmol) and potassium carbonate (12 g, 87.7 The mmol of tetrahydrofuran solution was stirred at reflux for 24 hours, filtered, dried and filtered to afford product. (1.7 g, 42% yield) . MS: 372 (M+H+).
N (2-氯 - (4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-6- (三氟甲基）苯基) -3,3-二甲基丁酰胺（化 合物 164)  N (2-Chloro-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-6-(trifluoromethyl)phenyl)-3,3-di Methylbutyramide (compound 164)
化合物 164B (319 mg， 0.86 mmol)、 1，2，3，4-四氢吡咯 [1，2-α]吡嗪 (100 mg， 0.82 mmol), Pd(AcO)2 (18 mg， 0.082 mmol)、 BINAP (51 mg， 0.082 mmol)、及碳酸铯 (650 mg， 2 mmol)溶于 6 mLl，4-二氧六环中， 反应液于封管中 110°C反应 3 h， 反应完成后， 过滤除去固体， 减压旋干 滤液， 剩余物制备分离纯化得目标化合物（20 mg， 5% 收率）。 1H NMR (400 MHz, CDC13) δ: 7.12-7.11(m, 1H), 7.06-7.05 (m, 1H), 6.71 (s, 1H), 6.64-6.63 (m, 1H), 6.20-6.18 (m, 1H), 6.00 (s, 1H), 4.48 (s, 2H), 4.12 (t, J = 11, 2H), 3.69 (t, J = 11, 2H), 2.29 (s, 2H), 1.14 (s, 9H). MS: 414 (M+H+). Compound 164B (319 mg, 0.86 mmol), 1,2,3,4-tetrahydropyrrole [1,2-α]pyrazine (100 mg, 0.82 mmol), Pd(AcO) 2 (18 mg, 0.082 mmol) BINAP (51 mg, 0.082 mmol) and cesium carbonate (650 mg, 2 mmol) were dissolved in 6 mL of 1,2-dioxane. The reaction solution was reacted at 110 ° C for 3 h in a sealed tube. After the reaction was completed, The solid was removed by filtration, and the filtrate was evaporated to dryness. 1H NMR (400 MHz, CDC1 3 ) δ: 7.12-7.11 (m, 1H), 7.06-7.05 (m, 1H), 6.71 (s, 1H), 6.64-6.63 (m, 1H), 6.20-6.18 (m , 1H), 6.00 (s, 1H), 4.48 (s, 2H), 4.12 (t, J = 11, 2H), 3.69 (t, J = 11, 2H), 2.29 (s, 2H), 1.14 (s , 9H). MS: 414 (M+H+).
实施例一百六十五  Example one hundred sixty five
N- (2-氯 -4- (3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))- 6-甲基苯基) -3,3-二甲基丁酰胺的制备
Figure imgf000127_0002
N-(2-chloro-4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-6-methylphenyl)-3,3-dimethylbutanamide Preparation
Figure imgf000127_0002
N- (4-溴 -2-氯 -6-甲基苯基） -3， 3-二甲基丁酰胺 （化合物 165A)  N-(4-Bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (Compound 165A)
0 。C， 2-氯 -6-甲基 -4-溴 -苯胺 (2.19 g， 10 mmol)和三乙胺 (3.5 mL， 25 mmol)的二氯甲烷溶液 中，加入 3， 3-二甲基丁酰氯 (2.1 ml, 15 mmol), 反应液室温搅拌 12小时后， 碳酸钠终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 过柱得产物。 （2.1 g，68% 收率) . MS: 328 (M+H+). 0. C, 2-Chloro-6-methyl-4-bromo-phenylamine (2.19 g, 10 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane 3, 3-Dimethylbutyryl chloride (2.1 ml, 15 mmol) was added. After the reaction mixture was stirred at room temperature for 12 hr, sodium carbonate was then evaporated, and ethyl acetate was evaporated, filtered, dried, and evaporated. (2.1 g, 68% yield). MS: 328 (M+H + ).
N- (2-氯—4- (3，4-二氢吡咯[1，2-0 |吡嗪-2( )- 6-甲基苯基) -3,3-二甲基丁酰胺（化合物 165 ) 本品由化合物 165A(273 mg, 0.86 mmol)和 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 (100 mg， 0.82 mmol) 按照化合物 115的制备方法合成， 封管中 90°C反应 2 h， 纯化得目标化合物 （20 mg， 6% 收 率） 。 1H NMR (400 MHz, CDC13) δ: 7.01 (s, 1H)， 7.00 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 6.64 (s, 1H), 6.21 (s, 1H), 6.01 (s, 1H)， 4.48 (s, 2H), 4.14 (t, J = 11, 2H), 3.68 (t，J = 11, 2H), 2.31 (s, 2H), 2.27 (s， 3H), 1.15 (s， 9H). MS: 360 (M+H+). N - (2-chloro-4-(3,4-dihydropyrrole[1,2-0 |pyrazine-2()-6-methylphenyl)-3,3-dimethylbutanamide (compound) 165) This product is synthesized from compound 165A (273 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (100 mg, 0.82 mmol) according to the preparation method of compound 115. The reaction was carried out at 90 ° C for 2 h, and the title compound was obtained (20 mg, 6% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 7.01 (s, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 6.64 (s, 1H), 6.21 (s, 1H), 6.01 (s, 1H), 4.48 (s, 2H), 4.14 (t, J = 11, 2H ), 3.68 (t, J = 11, 2H), 2.31 (s, 2H), 2.27 (s, 3H), 1.15 (s, 9H). MS: 360 (M+H + ).
实施例一百六十六  Example one hundred sixty six
N-(4-C3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2-甲氧 -6-甲基苯基) -3,3-二甲基丁酰胺的制备
Figure imgf000128_0001
N-(4-C3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide Preparation
Figure imgf000128_0001
N-(4-溴 -2-甲氧基 -6-甲基苯基) -3,3-二甲基丁酰胺 （化合物 166A)  N-(4-Bromo-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (Compound 166A)
4-溴 -2-甲氧基 -6-甲基苯胺 （50 mg，0.23 mmol)和 3,3-二甲基丁酰氯（53 mg，0.4 mmol)溶 于四氢呋喃 10 ml，加入碳酸钾 （70 mg，0.5 mmol) ，常温搅拌 4小时。 用乙酸乙酯萃取干燥， 浓 缩干过硅胶柱得目标化合物 64 mg。  4-bromo-2-methoxy-6-methylaniline (50 mg, 0.23 mmol) and 3,3-dimethylbutyryl chloride (53 mg, 0.4 mmol) dissolved in tetrahydrofuran (10 ml). Mg, 0.5 mmol), stirred at room temperature for 4 hours. It was extracted with ethyl acetate and concentrated to dryness over silica gel to give the title compound 64 mg.
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2-甲氧基 -6-甲基苯基) -3,3-二甲基丁酰胺 （化合 物 166)  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2-methoxy-6-methylphenyl)-3,3-dimethyl Butyramide (Compound 166)
本品由化合物 166A (64 mg, 0.2 mmol)禾口 1，2，3，4-四氢吡咯 [ l，2-a ]吡嗪 (37 mg, 0.3 mmol), 按照化合物 120的制备方法合成， 氮气保护下 120度反应 4 小时， 得目标产物 （50 mg, 产率 70% )。 MS:m/z=356(M+H+) o 1H NMR (400 MHz, DMSO) δ: 8.68(s， 1H), 6.67(s, 1H)， 6.44-6.50(m, 2H), 6.0 l(t, 1H), 5.85(s, 1H), 4.36(s, 2H), 4.02-4.07(m, 2H),3.72(s, 3H), 3.63(t, 2H), 2.08(s, 2H) 1.04 (s, 9H). This product is synthesized from compound 166A (64 mg, 0.2 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a ]pyrazine (37 mg, 0.3 mmol) according to the preparation method of compound 120. The reaction was carried out at 120 ° for 4 hours under a nitrogen atmosphere to give the desired product (50 mg, yield 70%). MS: m/z = 356 (M + H + ) o 1H NMR (400 MHz, DMSO) δ: 8.68 (s, 1H), 6.67 (s, 1H), 6.44-6.50 (m, 2H), 6.0 l ( t, 1H), 5.85(s, 1H), 4.36(s, 2H), 4.02-4.07(m, 2H), 3.72(s, 3H), 3.63(t, 2H), 2.08(s, 2H) 1.04 ( s, 9H).
实施例一百六十七  Example one hundred and sixty seven
N-(4-(3，4-二氢吡咯 [1，2-β]吡嗪 -2(iH))-2，6-二甲氧基苯基 )-3,3-二甲基丁酰胺（化合物 167) 的制备 N-(4-(3,4-dihydropyrrole[1,2- β ]pyrazine-2(iH))-2,6-dimethoxyphenyl)-3,3-dimethylbutanamide Preparation of (Compound 167)
Figure imgf000128_0002
本品由 N- (4-溴 -2，6-二甲氧基苯基） -3,3-二甲基丁酰胺 (284 mg， 0.86 mmol)和 1，2，3，4-四 氢吡咯 [l，2-a]吡嗪 ClOO mg, 0.82 mmol) 按照化合物 115的制备方法合成，封管中 90°C反应 3 h， 得目标化合物（40 mg， 13% 收率）。1H NMR (400 MHz, CDC13) δ: 6.61 (s, 1H), 6.37 (s, 1H), 6.18 (m， 3H), 5.96 (s, 1H), 4.41 (s, 2H), 4.09 (t, J = 11, 2H), 3.81 (s, 6H)， 3.64 (t, J = 11, 2H), 2.25 (s, 2H), 1.12 (s， 9H). MS: 372 (M+H+).
Figure imgf000128_0002
This product consists of N-(4-bromo-2,6-dimethoxyphenyl)-3,3-dimethylbutanamide (284 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine ClOO mg, 0.82 mmol) was synthesized according to the preparation method of Compound 115, and the mixture was reacted at 90 ° C for 3 h to obtain the target compound (40 mg, 13% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 6.61 (s, 1H), 6.37 (s, 1H), 6.18 (m, 3H), 5.96 (s, 1H), 4.41 (s, 2H), 4.09 (t, J = 11, 2H), 3.81 (s, 6H), 3.64 (t, J = 11, 2H), 2.25 (s, 2H), 1.12 (s, 9H). MS: 372 (M+H + ).
实施例一百六十八  Example one hundred and sixty eight
N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二乙基苯基) -3，3-二甲基丁酰胺 （化合物 168 ) 的制备  N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-diethylphenyl)-3,3-dimethylbutanamide ( Preparation of compound 168)
Figure imgf000129_0001
Figure imgf000129_0001
本品由 N- (4-溴 -2,6-二乙基苯基） -3,3-二甲基丁酰胺 (280 mg， 0.86 mmol)和 1，2，3，4-四氢 吡咯 [l，2-a]吡嗪 C100 mg，0.82 mmol) 按照化合物 115的制备方法合成，封管中 110°C反应 3 h， 得目标化合物 (20 mg， 6% 收率）。 1H NMR (400 MHz, CDC13) δ: 6.73(s, 2H), 6.60 (s, 1H), 6.50 (s, 1H)， 6.19-6.17 (m， 1H), 5.95 (s, 1H), 4.42 (s, 2H), 4.10 (t, J = 11, 2H), 3.64 (t, J = 11, 2H), 2.60-2.54 (m， 4H)， 2.29 (s， 2H), 1.25-1.21 (m， 6H)， 1.17 (s， 9H). MS: 368 (M+H+). This product consists of N-(4-bromo-2,6-diethylphenyl)-3,3-dimethylbutanamide (280 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [ l,2-a]pyrazine C100 mg, 0.82 mmol) was synthesized according to the preparation method of compound 115, and reacted at 110 ° C for 3 h to obtain the target compound (20 mg, 6% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 6.73 (s, 2H), 6.60 (s, 1H), 6.50 (s, 1H), 6.19-6.17 (m, 1H), 5.95 (s, 1H), 4.42 ( s, 2H), 4.10 (t, J = 11, 2H), 3.64 (t, J = 11, 2H), 2.60-2.54 (m, 4H), 2.29 (s, 2H), 1.25-1.21 (m, 6H) ), 1.17 (s, 9H). MS: 368 (M+H + ).
实施例一百六十九  Example one hundred sixty nine
Ν-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2-甲基苯基) -3，3-二甲基丁酰胺 （化合物 169) 的制 备
Figure imgf000129_0002
Ν-(4-(3,4-Dihydropyrrole[1,2-α]pyrazine-2(iH))-2-methylphenyl)-3,3-dimethylbutanamide (Compound 169) Preparation
Figure imgf000129_0002
本品由 N- (4-溴 -2 -甲基苯基） -3,3-二甲基丁酰胺 (243 mg， 0.86 mmol)和 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 (100 mg， 0.82 mmol) 按照化合物 115的制备方法合成， 封管中 110°C反应 3 h， 纯 化得目标化合物（80 mg， 30% 收率）。1H NMR (400 MHz, CDC13) δ: 7.55-7.53(m, 1Η), 6.83-6.82 (m, 2H), 6.80 (s, 1H), 6.60-6.59 (m, 1H), 6.18-6.17 (m, 1H), 5.95-5.94 (m, 1H), 4.38 (s, 2H), 4.08 (t J= 11， 2H), 3.61 (t， J= 11, 2H), 2.24 (s， 5H)， 1.12 (s， 9H). MS: 327 (M+H+). This product consists of N-(4-bromo-2-methylphenyl)-3,3-dimethylbutanamide (243 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [l,2 -a] Pyrazine (100 mg, 0.82 mmol) was synthesized according to the preparation method of Compound 115, and the mixture was subjected to a reaction at 110 ° C for 3 h to obtain the target compound (80 mg, 30% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 7.55-7.53 (m, 1 Η), 6.83-6.82 (m, 2H), 6.80 (s, 1H), 6.60-6.59 (m, 1H), 6.18-6.17 (m , 1H), 5.95-5.94 (m, 1H), 4.38 (s, 2H), 4.08 (t J= 11, 2H), 3.61 (t, J= 11, 2H), 2.24 (s, 5H), 1.12 ( s, 9H). MS: 327 (M+H + ).
实施例一百七十  Example one hundred and seventy
N- (2-氯 -(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))苯基) -3，3-二甲基丁酰胺 （化合物 170) 的制 备
Figure imgf000130_0001
N-(2-Chloro-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))phenyl)-3,3-dimethylbutanamide (Compound 170) Preparation
Figure imgf000130_0001
本品由 N- (4-溴 -2-氯苯基） -3,3-二甲基丁酰胺 (260 mg， 0.86 mmol)和 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 C100 mg，0.82 mmol) 按照化合物 115的制备方法合成， 封管中 90°C反应 3 h， 纯化 得目标化合物 (62 mg， 24% 收率） 。 1H NMR (400 MHz, CDC13) δ: 8.19-8.16(m, 1H), 7.32 (s， 2H), 6.96-6.95 (m， 1H)， 6.89-6.86 (m， 1H)， 6.60 (s, 1H)， 6.19-6.17 (m， 1H)， 5.97 (s, 1H)， 4.39 (s, 2H), 4.09 (t，J= 11, 2H), 3.61 (t，J= 11, 2H), 2.26 (s， 2H), 1.12 (s， 9H). MS: 347 (M+H+). This product consists of N-(4-bromo-2-chlorophenyl)-3,3-dimethylbutanamide (260 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [l,2- a] pyrazine C100 mg, 0.82 mmol) was synthesized according to the preparation method of compound 115, and the reaction was carried out at 90 ° C for 3 h in a sealed tube to obtain the target compound (62 mg, 24% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 8.19-8.16 (m, 1H), 7.32 (s, 2H), 6.96-6.95 (m, 1H), 6.89-6.86 (m, 1H), 6.60 (s, 1H ), 6.19-6.17 (m, 1H), 5.97 (s, 1H), 4.39 (s, 2H), 4.09 (t, J= 11, 2H), 3.61 (t, J= 11, 2H), 2.26 (s , 2H), 1.12 (s, 9H). MS: 347 (M+H+).
实施例一百七 ^一  Example one hundred seven ^ one
3-环戊基 -N-(4- 3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)丙酰胺的制备
Figure imgf000130_0002
Preparation of 3-cyclopentyl-N-(4- 3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)propanamide
Figure imgf000130_0002
N- (4-溴 -2,6-二甲基苯基） -3-环戊基丙酰胺 （化合物 171A)  N-(4-Bromo-2,6-dimethylphenyl)-3-cyclopentylpropanamide (Compound 171A)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 (2 g， 10 mmol)和三乙胺 (3.5 mL， 25 mmol)的二氯甲烷溶液 中， 加入 3-环戊基丙酰氯 (2.4 g， 15 mmol), 反应液室温搅拌 12小时后， 碳酸钠终止溶液， 乙 酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物。 （3 g，93% 收率) . MS: 324 (M+H+). Add 3-cyclopentylpropane to a solution of 0 °C, 2,6-dimethyl-4-bromo-phenylamine (2 g, 10 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane The acid chloride (2.4 g, 15 mmol) was stirred at room temperature for 12 hr. (3 g, 93% yield). MS: 324 (M+H + ).
3-环戊基 -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)丙酰胺的制备 （化合物 Preparation of 3-cyclopentyl-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)propanamide ( Compound
171 ) 171)
本品由化合物 171A(278 mg， 0.86 mmol)和 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 (100 mg， 0.82 mmol) 按照化合物 115的制备方法合成，封管中 120°C反应 8 h，纯化得目标化合物（115 mg， 38% 收 率）。 NMR (400 MHz, CDC13) δ: 6.68 (s, 2Η), 6.62-6.59 (m, 1H), 6.57 (brs, 1H), 6.19-6.17 (m, 1H), 5.97-5.94 (m， 1H)， 4.39 (s, 2H), 4.08 (t， J = 11， 2H),3.62 (t, J = 11， 2H), 2.43-2.39 (m， 2H), 2.23 (s， 6H)， 1.85-1.53 (m， 11). MS: 366 (M+H+). This product is synthesized from compound 171A (278 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (100 mg, 0.82 mmol) according to the preparation method of compound 115, sealing tube The reaction was carried out at 120 ° C for 8 h, and the title compound (115 mg, 38% yield) was obtained. NMR (400 MHz, CDC1 3 ) δ: 6.68 (s, 2Η), 6.62-6.59 (m, 1H), 6.57 (brs, 1H), 6.19-6.17 (m, 1H), 5.97-5.94 (m, 1H) , 4.39 (s, 2H), 4.08 (t, J = 11, 2H), 3.62 (t, J = 11, 2H), 2.43-2.39 (m, 2H), 2.23 (s, 6H), 1.85-1.53 ( m, 11). MS: 366 (M+H + ).
实施例一百七十二  Example one hundred seventy two
3-环己基 -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)丙酰胺的制备
Figure imgf000130_0003
Preparation of 3-cyclohexyl-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)propanamide
Figure imgf000130_0003
N- (4-溴 -2,6-二甲基苯基） -3-环己基丙酰胺 （化合物 172A)  N-(4-Bromo-2,6-dimethylphenyl)-3-cyclohexylpropanamide (Compound 172A)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 (1.5 g， 7.5 mmol)和三乙胺 (2.6 mL， 25 mmol)的二氯甲烷溶 液中，加入 3-环己基丙酰氯 (1.8 ml, 11.3 mmol),反应液室温搅拌 12小时后，碳酸钠终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物。 （2 g， 80% 收率) . MS: 338 (M+H+). 0 °C, 2,6-dimethyl-4-bromo-aniline (1.5 g, 7.5 mmol) and triethylamine (2.6 mL, 25 mmol) in dichloromethane To the solution, 3-cyclohexylpropanoyl chloride (1.8 ml, 11.3 mmol) was added, and the mixture was stirred at room temperature for 12 hr. (2 g, 80% yield) . MS: 338 (M+H + ).
3-环己基 -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)丙酰胺 （化合物 172) 本品由化合物 172A(290 mg， 0.86 mmol)和 1，2，3，4-四氢吡咯 [1，2-α]吡嗪 (100 mg， 0.82 mmol) 按照化合物 115的制备方法合成，封管中 120°C反应 8 h，纯化得目标化合物（100 mg， 32% 收 率）。 NMR (400 MHz, CDC13) δ: 6.71 (s, 2Η), 6.69-6.60 (m, 1H), 6.57 (brs, 1H), 6.19-6.17 (m, 1H), 5.97-5.95 (m， 1H), 4.41 (s， 2H), 4.09 (t， J = 11, 2H), 3.62 (t， J = 11, 2H), 2.42-2.38 (m， 2H), 2.22 (s， 6H)， 1.78-1.14 (m， 13H). MS: 380 (M+H+). 3-cyclohexyl-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)propanamide (compound 172) This product is synthesized from compound 172A (290 mg, 0.86 mmol) and 1,2,3,4-tetrahydropyrrole [1,2-α]pyrazine (100 mg, 0.82 mmol) according to the preparation method of compound 115, sealing tube The reaction was carried out at 120 ° C for 8 h, and the title compound was obtained (100 mg, 32% yield). NMR (400 MHz, CDC1 3 ) δ: 6.71 (s, 2Η), 6.69-6.60 (m, 1H), 6.57 (brs, 1H), 6.19-6.17 (m, 1H), 5.97-5.95 (m, 1H) , 4.41 (s, 2H), 4.09 (t, J = 11, 2H), 3.62 (t, J = 11, 2H), 2.42-2.38 (m, 2H), 2.22 (s, 6H), 1.78-1.14 ( m, 13H). MS: 380 (M+H + ).
实施例一百七十三  Example one hundred and seventy three
3-环戊基 -N- 4- 3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)丙酰胺的制备
Figure imgf000131_0001
Preparation of 3-cyclopentyl-N-4- 4,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)propanamide
Figure imgf000131_0001
二环 [2.2.1]己烷 -2-甲酰氯 （化合物 173A)  Bicyclo [2.2.1] hexane -2-carbonyl chloride (compound 173A)
0 °〇和氮气保护下， 二环 [2.2.1]己烷 -2-甲酸 (2.5 g， 17.8 mmol)的二氯甲烷溶液中， 加入草 酰氯 (1.8 ml, 21.4 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。  Oxalyl chloride (1.8 ml, 21.4 mmol) was added to a solution of bicyclo[2.2.1]hexane-2-carboxylic acid (2.5 g, 17.8 mmol) in m. After 2 hours, the product was obtained by spin-drying and used directly for the next reaction.
N- (4-溴 -2,6-二甲基苯基） 二环 [2.2.1]己烷 -2-甲酰胺 （化合物 173B)  N-(4-Bromo-2,6-dimethylphenyl)bicyclo[2.2.1]hexane-2-carboxamide (Compound 173B)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 (2.8 g， 14 mmol)和三乙胺 (4.9 mL， 35 mmol)的二氯甲烷溶液 中， 加入化合物 173A(2.4 g， 15 mmol), 反应液室温搅拌 12小时后， 碳酸氢钠终止溶液， 乙 酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物。 （3.8 g，86% 收率) . MS: 322 (M+H+). To a solution of 0 °C, 2,6-dimethyl-4-bromo-phenylamine (2.8 g, 14 mmol) and triethylamine (4.9 mL, 35 mmol) in dichloromethane After the reaction mixture was stirred at room temperature for 12 hrs, then the mixture was evaporated and evaporated. (3.8 g, 86% yield). MS: 322 (M+H + ).
3-环戊基 -Ν-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)丙酰胺 （化合物 173 ) 本品由化合物 173B (552 mg， 1.7 mmol)和 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 (200 mg， 1.6 mmol) 按照化合物 115的制备方法合成，封管中 110°C反应 3 h，纯化得目标化合物（260 mg， 45% 收 率） 。 1H NMR (400 MHz, CDC13) δ: 6.67 (s， 2H), 6.62-6.59 (m， 1H)， 6.55 (s， 1H)， 6.18-6.16 (m， 1H), 5.97-5.94 (m， 1H), 4.38 (s, 2H), 4.07 (t, J = 11, 2H), 3.60 (t, J = 11, 2H), 2.58-2.56 (m， 1H)， 2.38-2.34 (m， 2H), 2.05 (s, 6H)， 2.03-1.99 (m， 1H), 1.64-1.50 (m， 5H)， 1.33-1.20 (m， 2H). MS: 364 (M+H+). 3-cyclopentyl-indole-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)propanamide (compound 173 This product is synthesized from compound 173B (552 mg, 1.7 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (200 mg, 1.6 mmol) according to the preparation method of compound 115. The reaction was carried out at 110 ° C for 3 h in a tube to purify the target compound (260 mg, 45% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 6.67 (s, 2H), 6.62-6.59 (m, 1H), 6.55 (s, 1H), 6.18-6.16 (m, 1H), 5.97-5.94 (m, 1H ), 4.38 (s, 2H), 4.07 (t, J = 11, 2H), 3.60 (t, J = 11, 2H), 2.58-2.56 (m, 1H), 2.38-2.34 (m, 2H), 2.05 (s, 6H), 2.03-1.99 (m, 1H), 1.64-1.50 (m, 5H), 1.33-1.20 (m, 2H). MS: 364 (M+H+).
实施例一百七十四  Example one hundred and seventy four
2-金刚烷基 -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2，6-二甲基苯基)乙酰胺的制备
Figure imgf000132_0001
Preparation of 2-adamantyl-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2,6-dimethylphenyl)acetamide
Figure imgf000132_0001
2-金刚烷基 -N-(4-溴 -2，6-二甲基苯基)乙酰胺 （化合物 174A)  2-adamantyl-N-(4-bromo-2,6-dimethylphenyl)acetamide (Compound 174A)
4-溴 -2,6-二甲基胺 （50 mg，0.25 mmol)和 2-金刚烷基乙酰氯 （85 mg，0.4 mmol)溶于四氢 呋喃 10 ml，加入碳酸钾 （70 mg，0.5 mmol) ，常温搅拌 4小时。 用乙酸乙酯萃取干燥， 浓縮干过 硅胶柱得目标化合物 66 mg。  4-Bromo-2,6-dimethylamine (50 mg, 0.25 mmol) and 2-adamantylacetyl chloride (85 mg, 0.4 mmol) dissolved in tetrahydrofuran (10 ml), then potassium carbonate (70 mg, 0.5 mmol) Stir at room temperature for 4 hours. It was extracted with ethyl acetate and dried and concentrated to dryness to silica gel column.
2-金刚烷基 -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2，6-二甲基苯基)乙酰胺（化合物 174) 本品由化合物 174A (66 mg， 0.175 mmol)和 1，2，3，4-四氢吡咯 [ l，2-a ]吡嗪 (37 mg， 0.3 mmol) 按照化合物 120的制备方法合成， 在 N2保护下， 升温至 120度反应 4小时， 纯化得目标产物 （55 mg， 产率 75% ). MS:m/z=418(M+l 1H NMR (400 MHz, DMSO) δ: 8.86(s， 1H)， 6.72(s, 1H)， 6.65(t， 3H), 6.00(t， 3H), 5.84(d， 1H), 4.32(s, 1H), 4.00-4.04(m, 2H), 3.60(t, 2H), 2.11(d, 6H)， 2.04(s, 2H), 1.95(m, 3H), 1.59-1.70(m, 12H)。 2-adamantyl-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2,6-dimethylphenyl)acetamide (compound 174 This product is synthesized from compound 174A (66 mg, 0.175 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a ]pyrazine (37 mg, 0.3 mmol) according to the preparation method of compound 120. Under the N 2 protection, the reaction was heated to 120 °C for 4 hours to give the title compound (55 mg, yield 75%). MS: m/z = 418 (M+l 1H NMR (400 MHz, DMSO) δ: 8.86 ( s, 1H), 6.72(s, 1H), 6.65(t, 3H), 6.00(t, 3H), 5.84(d, 1H), 4.32(s, 1H), 4.00-4.04(m, 2H), 3.60 (t, 2H), 2.11 (d, 6H), 2.04 (s, 2H), 1.95 (m, 3H), 1.59-1.70 (m, 12H).
实施例一百七十五  Example one hundred seventy five
2-环戊基 -N- 4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2，6-二甲基苯基)乙酰胺的制备
Figure imgf000132_0002
Preparation of 2-cyclopentyl-N-4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2,6-dimethylphenyl)acetamide
Figure imgf000132_0002
N-(4-溴 -2,6-二甲基苯基) -2-环戊基乙酰胺 （化合物 175A)  N-(4-bromo-2,6-dimethylphenyl)-2-cyclopentylacetamide (Compound 175A)
4-溴 -2,6-二甲基胺 （50 mg，0.25 mmol)和 2-环戊基乙酰氯 （58 mg，0.4 mmol)溶于四氢呋 喃 10 ml，加入碳酸钾 （70 mg，0.5 mmol) ，常温搅拌 4小时。 用乙酸乙酯萃取干燥， 浓縮干过硅 胶柱得目标化合物 60 mg。  4-bromo-2,6-dimethylamine (50 mg, 0.25 mmol) and 2-cyclopentylacetyl chloride (58 mg, 0.4 mmol) were dissolved in tetrahydrofuran (10 ml) and potassium carbonate (70 mg, 0.5 mmol) Stir at room temperature for 4 hours. It was extracted with ethyl acetate and concentrated to dryness over silica gel to give the title compound 60 mg.
2-环戊基 -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2，6-二甲基苯基)乙酰胺 （化合物 175 ) 本品由化合物 175A (60 mg， 0.19 mmol)和 1，2，3，4-四氢吡咯 [ l，2-a ]吡嗪 (37 mg， 0.3 mmol) 按照化合物 120的制备方法合成， 在 N2保护下 120度反应 4小时， 反应结束减压旋干溶剂， 柱层 析纯化得目标产物 （50 mg， 产率 75% ). MS: 352 (M+H+)。 1H NMR (400 MHz, DMSO) δ: 8.94(s， 1H), 6.72(s, 2H)， 6.64-6.65(m, 1H), 5.99-6.01(m, 1H)， 5.83-5.84(m, 1H)， ,4.32 (s， 2H), 4.02(t, 2H), 3.60(t, 2H), 2.26(t, 2H), 1.78(m, 2H), 1.52-1.64(m, 4H)， 1.20-1.30(m, 3H). 2-cyclopentyl-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2,6-dimethylphenyl)acetamide (compound 175 This product is synthesized from compound 175A (60 mg, 0.19 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a ]pyrazine (37 mg, 0.3 mmol) according to the preparation method of compound 120. The reaction was carried out at a temperature of 120 ° C for 4 hours under N 2 , and then the solvent was evaporated to dryness, and purified by column chromatography to give the desired product (50 mg, yield 75%). MS: 352 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 8.94 (s, 1H), 6.72 (s, 2H), 6.64-6.65 (m, 1H), 5.99-6.01 (m, 1H), 5.83-5.84 (m, 1H) , , 4.32 (s, 2H), 4.02(t, 2H), 3.60(t, 2H), 2.26(t, 2H), 1.78(m, 2H), 1.52-1.64(m, 4H), 1.20-1.30 ( m, 3H).
实施例一百七十六  Example one hundred and seventy six
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2，6-二甲基苯基) -4-甲基戊酰胺的制备
Figure imgf000133_0001
Preparation of N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2,6-dimethylphenyl)-4-methylpentanamide
Figure imgf000133_0001
N-(4-溴 -2，6-二甲基苯基) -4-甲基戊酰胺 （化合物 176A)  N-(4-bromo-2,6-dimethylphenyl)-4-methylpentanamide (Compound 176A)
4-溴 -2,6-二甲基胺 （50 mg，0.25 mmol)和 4-甲基戊酰氯 （53 mg，0.4 mmol)溶于四氢呋喃 10 ml，加入碳酸钾 （70 mg，0.5 mmol) ，常温搅拌 4小时。 用乙酸乙酯萃取干燥， 浓縮干过硅胶 柱得目标化合物 66 mg。  4-bromo-2,6-dimethylamine (50 mg, 0.25 mmol) and 4-methylpentanoyl chloride (53 mg, 0.4 mmol) were dissolved in tetrahydrofuran (10 ml) and potassium carbonate (70 mg, 0.5 mmol). Stir at room temperature for 4 hours. It was extracted with ethyl acetate and concentrated to dryness over silica gel column to yield 66 mg.
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2 ( 1H) )-2，6-二甲基苯基) -4-甲基戊酰胺 （化合物 176) 本品由化合物 176A (60 mg， 0.2 mmol)和 1，2，3，4-四氢吡咯 [ l，2-a ]吡嗪 (37 mg， 0.3 mmol) 按照化合物 120的制备方法合成，在 N2保护下升温至 120度反应 4小时，反应结束减压旋干溶剂， 柱层析纯化得目标产物 （50 mg， 产率 74% ). MS:m/z=340(M+H+)。 1H NMR (400 MHz, DMSO) δ: 8.97(s, IH), 6.72(s, 2H)， 6.65(d， IH)， 6.00(t， IH)，5.84(d， IH), 4.32(d, 2H), 4.02(t,2H), 3.60(t,2H), 2.28(t, 2H), 2.13(d, 6H),1.47-1.60(m, 2H), 0.92(d, 6H). N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H))-2,6-dimethylphenyl)-4-methylpentanamide (Compound 176) This product is synthesized from compound 176A (60 mg, 0.2 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a ]pyrazine (37 mg, 0.3 mmol) according to the preparation of compound 120. heated to 120 degrees for 2 protection for 4 hours, the reaction was completed rotary evaporation under reduced pressure, purified by column chromatography to give the desired product (50 mg, yield 74%) MS:. m / z = 340 (m + H +). 1H NMR (400 MHz, DMSO) δ: 8.97 (s, IH), 6.72 (s, 2H), 6.65 (d, IH), 6.00 (t, IH), 5.84 (d, IH), 4.32 (d, 2H) ), 4.02(t,2H), 3.60(t,2H), 2.28(t, 2H), 2.13(d, 6H), 1.47-1.60(m, 2H), 0.92(d, 6H).
实施例一百七十七  Example one hundred seventy seven
N-(4-(3，4-二 -a]吡嗪 -2(1Η)-2，6-二甲基苯基) - -3-甲基丁酰胺的制备
Figure imgf000133_0002
Preparation of N-(4-(3,4-di-a)pyrazine-2(1Η)-2,6-dimethylphenyl)--3-methylbutanamide
Figure imgf000133_0002
3 -甲基丁酰氯 （化合物 177A)  3-methylbutyryl chloride (compound 177A)
3 -甲基丁酸（ 1.02 g， 10 mmol)溶于 20 mL无水二氯甲烷中，冰浴搅拌滴加入草酰氯（1.35 g， 11 mmol), 室温下搅拌 12 h。 滤液减压旋干， 得目标物为无色液体 （ 1.20 g， 100%收率）。 直接应用于下一步。  3-Methylbutyric acid (1.02 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. EtOAc (EtOAc, m. The filtrate was dried under reduced pressure to give a colorless liquid ( 1.20 g, 100% yield). Apply directly to the next step.
N-(4-溴 -2,6-二甲基苯基) -3-甲基丁酰胺 （化合物 177B)  N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide (Compound 177B)
化合物 177A ( 1.75g， 10 mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅拌加入 4-溴 -3， 5-二甲基苯胺 （2 g， 10 mmol), 三乙胺 (3 g， 30 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得浅黄色产物 （2.7 g， 97.9%) 。 MS: 285 (M+H+). Compound 177A (1.75 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at room temperature for 4 h. MS: 285 (M+H + ).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) - -3-甲基丁酰胺 （化合物 177) 本品由化合物 177B (0.81 g， 2.5 mmol)和 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪 (0.6 g， 2.5 mmol) 按照化合物 120的制备方法合成， 纯化得黄色目标产物 177 (405 mg， 51%收率）。 1H NMR (DMSO, 400MHz): δ 9.8.95 (s, IH), 6.72 (s, 2H), 6.64 (s, IH), 6.00 (s, IH), 5.80 (s, IH), 4.32 (s, 2H),4.01 (t， J = 4 Hz, 2H), 3.60 (t, J = 4 Hz, 2H), 2.15 (m， 2H), 2.12 (m， 7H)，0.95(d， J = 4 Hz, 6H).MS: 326 (M+H+). N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)--3-methylbutanamide (Compound 177) This product is synthesized from compound 177B (0.81 g, 2.5 mmol) and 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (0.6 g, 2.5 mmol) according to the preparation method of compound 120. Yellow target product 177 (405 mg, 51% yield). 1H NMR (DMSO, 400 MHz): δ 9. 8.95 (s, IH), 6.72 (s, 2H), 6.64 (s, IH), 6.00 (s , IH), 5.80 (s, IH), 4.32 (s, 2H), 4.01 (t, J = 4 Hz, 2H), 3.60 (t, J = 4 Hz, 2H), 2.15 (m, 2H), 2.12 (m, 7H), 0.95 (d, J = 4 Hz, 6H).MS: 326 (M+H+).
实施例一百七十八  Example one hundred seventy eight
N-(4-(3，4-二氢吡咯 l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) - -3-甲基戊酰胺的制备  Preparation of N-(4-(3,4-dihydropyrrole l,2-a)pyrazine-2(1Η)-2,6-dimethylphenyl)--3-methylpentanamide
Figure imgf000134_0001
Figure imgf000134_0001
3 -甲基戊酰氯 （化合物 178A)  3-methylpentanoyl chloride (compound 178A)
3 -甲基戊酸（ 1.16 g， 10 mmol)溶于 20 mL无水二氯甲烷中，冰浴搅拌滴加入草酰氯（1.35 g， 11 mmol), 室温下搅拌 12 h。 滤液减压旋干， 得目标物为无色液体 （ 1.34 g， 100%收率）。 直接应用于下一步。  3-Methylvaleric acid (1. 16 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. EtOAc (l. The filtrate was dried under reduced pressure to give a colourless liquid ( 1.34 g, 100% yield). Apply directly to the next step.
N-(4-溴 -2,6-二甲基苯基) -3-甲基戊酰胺 （化合物 178B)  N-(4-bromo-2,6-dimethylphenyl)-3-methylpentanamide (Compound 178B)
化合物 178A ( 1.34g， 10 mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅拌加入 4-溴 -3， 5- 二甲基苯胺 （2 g， 10 mmol), 三乙胺 (3 g， 30 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得浅 黄色产物 （2.7 g， 97.9%) 。 MS: 336 (M+H+).  Compound 178A ( 1.34 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. &lt;&quot;&gt;&gt;&gt;&gt;&gt; 4-bromo-3,5-dimethylaniline (2 g, 10 mmol), triethylamine (3 g) The reaction mixture was stirred at room temperature for 4 h. MS: 336 (M+H+).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) - -3-甲基戊酰胺 （化合物 178) 本品由化合物 178B (0.81 g， 2.5 mmol)和 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪 (0.6 g， 2.5mmol) 按照化合物 120的制备方法合成，纯化得黄色目标产物（405 mg，51%收率）。 1H NMR (DMSO, 400MHz): δ 8.96 (s, 1H), 6.78 (s, 2H), 6.65 (s, 1H), 6.00 (s, 1H), 5.84 (s, 1H), 4.33 (s, 2H),4.02 (t， J = 8 Hz, 2H), 3.60 (t， J = 8 Hz, 4H)， 2.25 (m， 1H.)， 2.06 (m， 7H), 1.91 (m， 1H), 1.37 (m， 1H), 1.23 (m， 1H), 0.90 (m， 6H.). MS: 340(M+H+). N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)--3-methylpentanamide (Compound 178) This product is synthesized from compound 178B (0.81 g, 2.5 mmol) and 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (0.6 g, 2.5 mmol) according to the preparation method of compound 120. Yellow target product (405 mg, 51% yield). 1H NMR (DMSO, 400 MHz): δ 8.96 (s, 1H), 6.78 (s, 2H), 6.65 (s, 1H), 6.00 (s, 1H) , 5.84 (s, 1H), 4.33 (s, 2H), 4.02 (t, J = 8 Hz, 2H), 3.60 (t, J = 8 Hz, 4H), 2.25 (m, 1H.), 2.06 (m , 7H), 1.91 (m, 1H), 1.37 (m, 1H), 1.23 (m, 1H), 0.90 (m, 6H.). MS: 340 (M+H + ).
实施例一百七十九  Example one hundred seventy nine
N-(4-(3 -二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -3-丁基苯） 乙酰胺的制备  Preparation of N-(4-(3-dihydropyrrole [l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-3-butylbenzene)acetamide
Figure imgf000134_0002
Figure imgf000134_0002
3 -苯基丁酰氯 （化合物 179A)  3-phenylbutyryl chloride (compound 179A)
3 -苯基丁酸（ 1.64 g， 10 mmol)溶于 20 mL无水二氯甲烷中，冰浴搅拌滴加入草酰氯（1.35 g， 11 mmol), 室温下搅拌 12 h。 滤液减压旋干， 得目标物为无色液体 （ 1.82 g， 100%收率）。 直接应用于下一步。 N-(4-溴 -2，6-二甲基苯基) -3-丁基苯 （化合物 179B) 3 -Phenylbutyric acid ( 1.64 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. EtOAc (1. The filtrate was dried under reduced pressure to give a colorless liquid (yield: 1.82 g, 100% yield). Apply directly to the next step. N- (4-bromo-2,6-dimethylphenyl)-3-butylbenzene (compound 179B)
化合物 179A ( 1.82g， 10 mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅拌加入 4-溴 -3， 5-二甲基苯胺 （2 g， 10 mmol), 三乙胺 (3 g， 30 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得浅黄色产物 （3.3 g， 97.9%) 。 MS: 346 (M+H+). Compound 179A (1.82 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. EtOAc (3 g, 10 mmol), triethylamine (3 g) The reaction mixture was stirred at room temperature for 4 h. MS: 346 (M+H + ).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -3-丁基苯） 乙酰胺 （化合物 179) 本品由化合物 179B (0.85 g， 2.5 mmol)和 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪 (0.6 g，2.5 mmol) 按照化合物 115的制备方法合成，氮气保护下加热回流 12小时，纯化得黄色目标产物 (480 mg， 49.5%收率）。 1H NMR (DMSO, 400ΜΗζ): δ 8.97 (s， 1H), 7.31 (m， 4H)， 7.19 (m， 1H), 6.65 (m， 2H) 6.00 (t, J= 4 Ηζ,ΙΗ), 5.80 (s, 1H), 4.31 (s, 2H),4.01 (t, J = 8 Hz, 2H), 3.58 (t， J = 8 Hz, 2H), 3.26 (m， 1H), 2.56 (m， 2H),1.26 (d, J= 8 Hz,3H). MS: 378 (M+H+).  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-3-butylbenzene)acetamide (compound 179 This product is synthesized from compound 179B (0.85 g, 2.5 mmol) and 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (0.6 g, 2.5 mmol) according to the preparation method of compound 115. The mixture was heated to reflux for 12 hours under nitrogen to give purified title product (yield: 480 mg, 49.5% yield). 1H NMR (DMSO, 400 ΜΗζ): δ 8.97 (s, 1H), 7.31 (m, 4H), 7.19 (m, 1H), 6.65 (m, 2H) 6.00 (t, J = 4 Ηζ, ΙΗ), 5.80 ( s, 1H), 4.31 (s, 2H), 4.01 (t, J = 8 Hz, 2H), 3.58 (t, J = 8 Hz, 2H), 3.26 (m, 1H), 2.56 (m, 2H), 1.26 (d, J= 8 Hz, 3H). MS: 378 (M+H+).
实施例一百八十  Example one hundred and eighty
Ν- 4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯基 3- (呋喃 -2-基)丙酰胺的制备
Figure imgf000135_0001
4-(3,4-Dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl 3-(furan-2-yl)propanamide Preparation
Figure imgf000135_0001
3- (呋喃 -2-基)丙酰氯 （化合物 180A)  3-(furan-2-yl)propanoyl chloride (Compound 180A)
在圆底烧瓶中加入 3- (；呋喃 -2-基)丙酸 （1.4 g， 10 mmol), 二氯甲烷 （15 mL), N，N-二 甲基甲酰胺 （0.1mL)。 草酰氯 （1.89g， 1.5mL)缓慢滴加到反应溶液中， 室温搅拌 2小时， 减压整出溶剂得到化合物 180A ( 1.6g, 收率 100%)。  To a round bottom flask was added 3-(;furan-2-yl)propanoic acid (1.4 g, 10 mmol), dichloromethane (15 mL), N,N-dimethylformamide (0.1mL). Oxalyl chloride (1.89 g, 1.5 mL) was slowly added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure to give compound 180A (1.6 g, yield: 100%).
N-(4-溴 -2,6-甲基苯基) -3- (呋喃 -2-基)丙酰胺 （化合物 180B)  N-(4-Bromo-2,6-methylphenyl)-3-(furan-2-yl)propanamide (Compound 180B)
在原定烧瓶中加入 4-溴 -2,6-二甲基苯胺（2 g， 10 mmol), 二氯甲烷 （40 mL)， 三乙胺 ( 1.5 g， 15 mmol), 3- (；呋喃 -2-基)丙酰氯 （1.6g， 10 mmol) 的二氯甲烷溶液 （20mL) 缓慢滴 加到反应液中， 室温搅拌 1小时， 减压蒸出溶剂， 加入 lOOmL乙酸乙酯， 稀盐酸 （20 mL) 洗涤， 饱和氯化钠 （20 mL) 洗涤， 无水硫酸钠干燥， 减压蒸出溶剂得到 N-(4-溴 -2,6-甲基苯 基) -3- (呋喃 -2-基)丙酰胺 （1.87 g， 58%) LCMS: 322 [M+H]+. Add 4-bromo-2,6-dimethylaniline (2 g, 10 mmol), dichloromethane (40 mL), triethylamine (1.5 g, 15 mmol), 3- (furan) A solution of 2-yl)propanoyl chloride (1.6 g, 10 mmol) in dichloromethane (20 mL) was slowly added dropwise to the reaction mixture, stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. Washed, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and evaporated evaporated.]]]~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -yl)propanamide (1.87 g, 58%) LCMS: 322 [M+H] + .
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2,6-二甲基苯基) -3- (呋喃 -2-基)丙酰胺 （化合物 N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3-(furan-2-yl) Propionamide
180) 180)
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 (122 mg， 1 mmol)和 N-(4-溴 -2,6-甲基苯基) -3- (呋喃 -2-基)丙酰胺 （322mg， 1 mmol) 按照化合物 120的制备方法合成， 得到目标化合物 (110mg， 收率 27.5%)。 MS: 360 [M+H]+. 1腿 MR (400MHz， DMSO) δ: 9.06(s，lH)， 7.53(s,lH), 6.71(s, 2H), 6.66-6.65(m,lH), 6.38-6.36 (m, 1H), 6.15-6.14 (m, 1H), 6.00 (t,lH, J=3.2Hz), 5.84-5.83 (m,lH): 4.32 (s, 2H), 4.02 (t， 2H, J=5.6Hz), 3.60 (t,2H, J=5.6Hz), 2.93 (t， 2H, J=7.6Hz), 2.62 (t， 2H: J=7.6Hz), 2.04 (s， 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-methylphenyl)-3 -(furan-2-yl)propanamide (322 mg, 1 mmol) was obtained according to the procedure of the compound 120 to give the title compound (110 mg, yield: 27.5%). MS: 360 [M+H]+. 1 leg MR (400MHz, DMSO) δ: 9.06(s,lH), 7.53(s,lH), 6.71(s, 2H), 6.66-6.65(m,lH), 6.38-6.36 (m, 1H), 6.15-6.14 (m, 1H), 6.00 (t,lH, J=3.2Hz), 5.84-5.83 (m,lH) : 4.32 ( s, 2H), 4.02 (t, 2H, J=5.6Hz), 3.60 (t, 2H, J=5.6Hz), 2.93 (t, 2H, J=7.6Hz), 2.62 (t, 2H : J=7.6 Hz), 2.04 (s, 6H).
实施例一百八 ^一  Example one hundred eight ^ one
N- 4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯基) -3-苯基乙酰胺的制备
Figure imgf000136_0001
Preparation of N-4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3-phenylacetamide
Figure imgf000136_0001
苯乙酰氯 （化合物 181 A)  Phenylacetyl chloride (Compound 181 A)
在圆底烧瓶中加入苯乙酸 （2.04 g， 15 mmol)， 二氯亚砜 （ 15 mL)， 回流 3小时， 减 压整出溶剂得到化合物 181 A (2.31g, 收率 100%)。  Phenylacetic acid (2.04 g, 15 mmol) and dichloromethane (15 mL) were added to a round bottom flask, and refluxed for 3 hr, and solvent was evaporated to give Compound 181 A (2.31 g, yield 100%).
N-(4-溴 -2,6-二甲基苯基) -3-苯基乙酰胺 （化合物 181B) N- (4-bromo-2,6-dimethylphenyl)-3-phenylacetamide (Compound 181B)
在圆底烧瓶中加入 4-溴 -2,6-二甲基苯胺 （2 g， lO mmol), 二氯甲烷 （40mL)， 三乙胺 ( 1.5 g， 15 mmol), 苯乙酰氯 （1.54g， 10 mmol) 的二氯甲烷溶液 （20mL) 缓慢滴加到反 应液中， 室温搅拌 1小时， 减压蒸出溶剂， 加入 lOOmL乙酸乙酯， 稀盐酸 （10 mL) 洗涤， 饱和氯化钠 （10 mL) 洗涤， 无水硫酸钠干燥， 减压蒸出溶剂得到 N-(4-(3，4-二氢吡咯 [l，2-a] 吡嗪 -2(1H)-基) -2,6-二甲基苯基) -3-苯基乙酰胺 （3g， 94.6%) MS: 318 [M+H]+. Add 4-bromo-2,6-dimethylaniline (2 g, 10 mmol), dichloromethane (40 mL), triethylamine (1.5 g, 15 mmol), phenylacetyl chloride (1.54 g). , 10 mmol) of dichloromethane solution (20 mL) was slowly added dropwise to the reaction mixture, stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and ethyl acetate (100 mL) was then evaporated. 10 mL) Washed, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2. 6-Dimethylphenyl)-3-phenylacetamide (3 g, 94.6%) MS: 318 [M+H] + .
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2,6-二甲基苯基) -3-苯基乙酰胺 （化合物 181 ) 本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪（122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯基) -3- 苯基乙酰胺（331mg， 1 mmol)按照化合物 120的制备方法合成，纯化得到目标化合物（ 110mg， 收率 35%)。 MS: 360 [M+H]+。 iHNMR (400MHz， DMSO) δ: 9.23 (s， 1H), 7.38-7.25 (m， 5H)， 6.71(s, 2H), 6.65 (t，lH， J=2Hz), 6.00 (t，lH， J=2.8Hz), 5.83 (s，lH)， 4.32 (s, 2H), 4.01 (t,2H, J=5.2Hz), 3.60-3.58 (m， 4H)， 2.04 (s, 6H)。  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3-phenylacetamide (compound) 181) This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl) -3-Phenylacetamide (331 mg, 1 mmol) was synthesized according to the procedure of Compound 120 to afford the title compound (110 mg, yield: 35%). MS: 360 [M+H]+. iHNMR (400MHz, DMSO) δ: 9.23 (s, 1H), 7.38-7.25 (m, 5H), 6.71(s, 2H), 6.65 (t,lH, J=2Hz), 6.00 (t,lH, J= 2.8 Hz), 5.83 (s, lH), 4.32 (s, 2H), 4.01 (t, 2H, J = 5.2 Hz), 3.60-3.58 (m, 4H), 2.04 (s, 6H).
实施例一百八十二  Example one hundred eighty two
N-(4-C3， -二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯基 3-苯基丙酰胺的制备
Figure imgf000136_0002
Preparation of N-(4-C3,-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl 3-phenylpropanamide
Figure imgf000136_0002
N-(4-溴 -2,6-二甲基苯基) -3-苯基丙酰胺 （化合物 182A)  N-(4-bromo-2,6-dimethylphenyl)-3-phenylpropanamide (compound 182A)
在圆底烧瓶中加入 4-溴 -2,6-二甲基苯胺 （2 g， lOmmol), 二氯甲烷 （40 mL)， 三乙 ( 1.5 g， 15mmol) 苯丙酰氯 （1.68g， lOmmol) 的二氯甲烷溶液 40mL缓慢滴加到反应溶 液中， 25°C搅拌 1小时。 加入乙酸乙酯 lOOmL, 稀盐酸 （5 mol/L) 洗涤， 无水硫酸钠干 燥， 减压整出溶剂得到化合物 182A (3.3g, 收率 99%)。 MS: 332 [M+H]+. Add 4-bromo-2,6-dimethylaniline (2 g, 10 mmol), dichloromethane (40 mL), triethyl (1.5 g, 15 mmol) phenylpropanoyl chloride (1.68 g, lOmmol). 40mL of dichloromethane solution is slowly added dropwise to the reaction solution The solution was stirred at 25 ° C for 1 hour. After adding ethyl acetate (100 mL), diluted with hydrochloric acid (5 mol/L), dried over anhydrous sodium sulfate, and the solvent was evaporated to give Compound 182A (3.3 g, yield 99%). MS: 332 [M+H] + .
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2,6-二甲基苯基) -3-苯基丙酰胺 （化合物 182) 本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 (122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯基) -3-苯 基丙酰胺（331mg， 1 mmol)按照化合物 120的制备方法合成， 纯化得到目标化合物（110mg， 收率 30%)。 MS: 374 [M+H] +。 ^MR (400MHz, DMSO) δ: 8.98 (s， 1H)， 7.32-7.18 (m， 5H)， 6.70 (s, 2H), 6.66-6.64 (m,lH), 6.01-6.00 (m,lH), 5.84 (s,lH), 4.32 (s, 2H), 4.02 (t, 2H, J=5.2Hz), 3.59 (t， 2H, J=5.2Hz), 2.92 (t， 2H, J= 7.2Hz), 2.61 (t， 2H, J=7.2), 1.99 (s， 6H)。  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3-phenylpropanamide (compound) 182) This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl) -3-Phenylpropionamide (331 mg, 1 mmol) was synthesized according to the procedure of Compound 120 to give the title compound (110 mg, yield 30%). MS: 374 [M+H] +. ^MR (400MHz, DMSO) δ: 8.98 (s, 1H), 7.32-7.18 (m, 5H), 6.70 (s, 2H), 6.66-6.64 (m, lH), 6.01-6.00 (m, lH), 5.84 (s,lH), 4.32 (s, 2H), 4.02 (t, 2H, J=5.2Hz), 3.59 (t, 2H, J=5.2Hz), 2.92 (t, 2H, J= 7.2Hz), 2.61 (t, 2H, J=7.2), 1.99 (s, 6H).
实施例一百八十三  Example one hundred eighty three
N-(4-(3，4-二 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -2- (4-氟苯基） 乙酰胺的制备  Preparation of N-(4-(3,4-bis[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-2-(4-fluorophenyl)acetamide
Figure imgf000137_0001
Figure imgf000137_0001
对氟苯乙酰氯 （化合物 183A)  P-fluorophenylacetyl chloride (compound 183A)
对氟苯乙酸（1.54 g， 10 mmol)溶于 20 mL无水二氯甲烷中，冰浴搅拌滴加入草酰氯（1.35 g， 11 mmol), 室温下搅拌 12 h。 滤液减压旋干， 得目标物为无色液体 （ 1.75 g， 100%收率）， 直接应用于下一步。  p-Fluorophenylacetic acid (1.54 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. oxalyl chloride (1.35 g, 11 mmol. The filtrate was dried under reduced pressure to give the object as a colorless liquid ( 1.75 g, 100% yield).
N-(4-溴 -3,5-二甲基苯基) -2- (4-氟苯基） 乙酰胺 （化合物 183B)  N-(4-bromo-3,5-dimethylphenyl)-2-(4-fluorophenyl)acetamide (compound 183B)
化合物 183A ( 1.75g， 10 mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅拌加入 4-溴 -3， 5-二甲基苯胺 （2 g， 10 mmol), 三乙胺 (3 g， 30 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得 浅黄色产物 (3.4 g, 97.9%) 。 MS: 336 (M+H)+. Compound 183A ( 1.75 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. EtOAc (3 g, 10 mmol), triethylamine (3 g) The reaction mixture was stirred at room temperature for 4 h. MS: 336 (M+H) + .
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -2- (4-氟苯基）乙酰胺（化合物 183 ) 本品由化合物 183B (0.85 g， 2.5 mmol)和 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪 (0.6 g， 2.5 mmol) 按照化合物 120的制备方法合成，纯化得黄色目标产物（455 mg， 49.5%收率）。1H NMR (DMSO 400MHz): δ 9.24 (s, 1H), 7.40 (dd, J= 8 Hz, 2H), 7.14 (dd， J= 8 Hz, 2H), 6.71 (s, 2H), 6.65 (s, 1H) 6.00 (s, 1H), 5.80 (s, 1H), 4.32 (s, 2H),4.01 (t, J= 8 Hz, 2H), 3.60 (m, 4H), 2.00 (s, 6H). MS: 378 (M+H+). MS: 378 (M+H+).  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-2-(4-fluorophenyl)acetamide (Compound 183) This product was prepared from compound 183B (0.85 g, 2.5 mmol) and 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (0.6 g, 2.5 mmol) according to compound 120 Method Synthesis: Purification of the title compound (455 mg, 49.5% yield). 1H NMR (DMSO 400MHz): δ 9.24 (s, 1H), 7.40 (dd, J = 8 Hz, 2H), 7.14 (dd, J = 8 Hz, 2H), 6.71 (s, 2H), 6.65 (s, 1H) 6.00 (s, 1H), 5.80 (s, 1H), 4.32 (s, 2H), 4.01 (t, J= 8 Hz, 2H), 3.60 (m, 4H), 2.00 (s, 6H). MS: 378 (M+H+). MS: 378 (M+H+).
实施例一百八十四  Example one hundred eighty four
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -2- (3-氟苯基） 乙酰胺的制备
Figure imgf000138_0001
N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-2-(3-fluorophenyl)acetamide Preparation
Figure imgf000138_0001
间氟苯乙酰氯 （化合物 184A)  M-fluorophenylacetyl chloride (compound 184A)
间氟苯乙酸（1.54 g， lO mmol)溶于 20 mL无水二氯甲烷中，冰浴搅拌滴加入草酰氯（ 1.35 g， ll mmol), 室温下搅拌 12 h。 滤液减压旋干， 得目标物为无色液体 （ 1.75 g， 100%收率）。 直接应用于下一步。  m-Fluorophenylacetic acid (1.54 g, 10 mmol) was dissolved in 20 mL of anhydrous dichloromethane. oxalyl chloride (1.35 g, ll mmol) was added dropwise with stirring in an ice bath and stirred at room temperature for 12 h. The filtrate was dried under reduced pressure to give a colorless liquid ( 1.75 g, 100% yield). Apply directly to the next step.
N-(4-溴 -2,6-二甲基苯基) -2- (3-氟苯基） 乙酰胺 （化合物 184B) N- (4-bromo-2,6-dimethylphenyl)-2-(3-fluorophenyl)acetamide (compound 184B)
化合物 184A ( 1.75g， 10 mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅拌加入 4-溴 -3， 5-二甲基苯胺 （2 g， lO mmol), 三乙胺 (3 g， 30 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得 浅黄色产物 （3.4 g， 97.9%) 。 MS: 336 (M+H+). Compound 184A ( 1.75 g, 10 mmol) was dissolved in 20 mL anhydrous dichloromethane. EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 4 h. MS: 336 (M+H + ).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -2- (3-氟苯基）乙酰胺（化合物 184) 本品由化合物 184B (0.85 g， 2.5 mmol)和 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪 (0.6 g， 2.5 mmol) 按照化合物 120的制备方法合成， 纯化得黄色产物 （450 mg， 49.5%收率）。 1H NMR (DMSO, 400MHz): δ 9.27 (s, 1H), 7.40 (m, 2H), 7.21 (m, 2H), 7.09 (s, 1H), 6.72 (s, 2H), 6.65 (s, 1H), 6.00 (s, 1H)， 5.84 (s, 1H)， 4.32 (s, 2H),4.01 (t， J = 8 Hz, 2H), 3.60 (m， 4H)， 2.00 (s, 6H). MS: 378 (M+H+).  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-2-(3-fluorophenyl)acetamide (Compound 184) This product was prepared from compound 184B (0.85 g, 2.5 mmol) and 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (0.6 g, 2.5 mmol) according to compound 120 Method of synthesis, purification of the yellow product (450 mg, 49.5% yield). 1H NMR (DMSO, 400 MHz): δ 9.27 (s, 1H), 7.40 (m, 2H), 7.21 (m, 2H), 7.09 (s , 1H), 6.72 (s, 2H), 6.65 (s, 1H), 6.00 (s, 1H), 5.84 (s, 1H), 4.32 (s, 2H), 4.01 (t, J = 8 Hz, 2H) , 3.60 (m, 4H), 2.00 (s, 6H). MS: 378 (M+H+).
实施例一百八十五  Example one hundred eighty five
N-(4-( -二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -2- (2-氟苯基） 乙酰胺的制备  Preparation of N-(4-(-dihydropyrrole [l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-2-(2-fluorophenyl)acetamide
Figure imgf000138_0002
Figure imgf000138_0002
邻氟苯乙酰氯 （化合物 185A)  O-fluorophenylacetyl chloride (compound 185A)
邻氟苯乙酸（1.54 g， 10 mmol)溶于 20 mL无水二氯甲烷中，冰浴搅拌滴加入草酰氯（1.35 g， ll mmol), 室温下搅拌 12 h。 滤液减压旋干， 得目标物为无色液体 （ 1.75 g， 100%收率）。 直接应用于下一步。  O-Fluorophenylacetic acid (1.54 g, 10 mmol) was dissolved in 20 mL of anhydrous dichloromethane. oxalyl chloride (1.35 g, ll mmol) was added dropwise with stirring in an ice bath and stirred at room temperature for 12 h. The filtrate was dried under reduced pressure to give a colorless liquid ( 1.75 g, 100% yield). Apply directly to the next step.
N-(4-溴 -2,6-二甲基苯基) -2- (2氟苯基） 乙酰胺 （化合物 185B)  N-(4-bromo-2,6-dimethylphenyl)-2-(2-fluorophenyl)acetamide (compound 185B)
化合物 185A ( 1.75g， lO mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅拌加入 4-溴 -3， 5- 二甲基苯胺 （2 g， 10 mmol), 三乙胺 (3 g， 30 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得浅 黄色产物 ( 3.4 g, 97.9%) 。 MS: 336 (M+H+). Compound 185A ( 1.75 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. &lt;RTI ID=0.0&gt;&gt; , 30 mmol) The reaction solution was stirred at room temperature for 4 h, and the filtrate was dried under reduced pressure. Yellow product (3.4 g, 97.9%). MS: 336 (M+H+).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1Η)-2，6-二甲基苯基) -2- (2-氟苯基）乙酰胺（化合物 185 ) 本品由化合物 185B ( 0.85 g， 2.5 mmol)和 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪 (0.6 g， 2.5 mmol) 按照化合物 120的制备方法合成，纯化得黄色目标产物（460 mg， 49.5%收率）。1H NMR (DMSO 400MHz): δ 9.42 (m, 1H), 7.30 (m, 1H), 7.16 (m, 2H), 6.73 (s, 2H), 5.84 (s, 1H), 4.33 (s, 2H), 4.02 (t， J= 8 Hz, 2H), 3.70 (s, 2H), 3.60 (m, 2H), 2.10 (s, 6H). MS: 378 (M+H+).  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1Η)-2,6-dimethylphenyl)-2-(2-fluorophenyl)acetamide (Compound 185) This product was prepared from compound 185B (0.85 g, 2.5 mmol) and 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (0.6 g, 2.5 mmol) according to compound 120 Method Synthesis and purification of the title compound (460 mg, 49.5% yield). 1H NMR (DMSO 400MHz): δ 9.42 (m, 1H), 7.30 (m, 1H), 7.16 (m, 2H), 6.73 (s , 2H), 5.84 (s, 1H), 4.33 (s, 2H), 4.02 (t, J= 8 Hz, 2H), 3.70 (s, 2H), 3.60 (m, 2H), 2.10 (s, 6H) MS: 378 (M+H+).
实施例一百八十六  Example one hundred eighty six
2-(3-氯苯基 -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺的制备  2-(3-Chlorophenyl-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)acetamide Preparation
Figure imgf000139_0001
Figure imgf000139_0001
2-(3-氯苯基)乙酰氯 （化合物 186A)  2-(3-chlorophenyl)acetyl chloride (compound 186A)
0 °〇和氮气保护下， 2- 3-氯苯基)乙酸 3.4 g，20 mmol) 的二氯甲烷溶液中， 加入草酰氯 (2 ml, 22 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。  Oxalyl chloride (2 ml, 22 mmol) was added to a solution of 2-chlorophenyl)acetic acid (3.4 g, 20 mmol) in dichloromethane (2 mL). The product was obtained as a dry solution and used directly in the next reaction.
N-(4-溴 -2,6-二甲基苯基) -2-(3-氯苯基)乙酰胺 （化合物 186B)  N-(4-bromo-2,6-dimethylphenyl)-2-(3-chlorophenyl)acetamide (compound 186B)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 （3.64 g， 18.2 mmol) 和三乙胺 （6.4 mL， 45.5 mmol)的二氯 甲烷溶液中， 加入 2- 3-氯苯基)乙酰氯 C3.78 g， 20 mmol), 反应液室温搅拌 12小时后， 碳酸 氢钠终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物 (3.8 g， 63% 收率)。  Add 2-chlorobenzene to a solution of 0 °C, 2,6-dimethyl-4-bromo-phenylamine (3.64 g, 18.2 mmol) and triethylamine (6.4 mL, 45.5 mmol) in dichloromethane Acetyl chloride C3.78 g, 20 mmol). After the reaction mixture was stirred at room temperature for 12 hrs, sodium bicarbonate was evaporated, ethyl acetate was evaporated, filtered, dried, evaporated, evaporated. rate).
2-(3-氯苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺 （化合物 186) 本品由 N-(4-溴 -2,6-二甲基苯基) -2-(3-氯苯基)乙酰胺 （526 mg， 1.5 mmol)和 1，2，3，4-四氢吡 咯 [l，2-a]吡嗪 （122 mg， 1 mmol) 按照化合物 115的制备方法合成， 封管中 110°C反应 3 h， 纯 化得目标化合物 (50 mg， 13% 收率）。 1H NMR (400 MHz, CDC13) δ: 7.40 (s, 1H), 7.28-7.34 (m, 3H), 6.63 (s， 2H), 6.58-6.59 (m， 1H), 6.48 (s， 1H), 6.582 (t， J= 2.8, 1H), 5.93-5.94 (m， 1H), 4.37 (s， 2H), 4.060 (t， J= 5.2, 2H), 3.74 (s， 2H), 3.594 (t， J= 5.2, 2H), 2.10 (s， 6H)。 MS: 394 (M+H+)。 2-(3-Chlorophenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)B Amide (Compound 186) This product consists of N-(4-bromo-2,6-dimethylphenyl)-2-(3-chlorophenyl)acetamide (526 mg, 1.5 mmol) and 1,2,3 , 4-tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol) was synthesized according to the preparation method of compound 115, and sealed at 110 ° C for 3 h to obtain the target compound (50 mg, 13%). Yield). 1H NMR (400 MHz, CDC1 3 ) δ: 7.40 (s, 1H), 7.28-7.34 (m, 3H), 6.63 (s, 2H), 6.58-6.59 (m, 1H), 6.48 (s, 1H), 6.582 (t, J= 2.8, 1H), 5.93-5.94 (m, 1H), 4.37 (s, 2H), 4.060 (t, J= 5.2, 2H), 3.74 (s, 2H), 3.594 (t, J = 5.2, 2H), 2.10 (s, 6H). MS: 394 (M+H + ).
实施例一百八十七  Example one hundred eighty seven
2-
Figure imgf000139_0002
2-
Figure imgf000139_0002
2-(3-溴苯基)乙酰氯 （化合物 187A)  2-(3-bromophenyl)acetyl chloride (Compound 187A)
0 °〇和氮气保护下， 2-(3-溴苯基)乙酸 （215 mg， 1 mmol) 的二氯甲烷溶液中，加入草酰氯 (0.1 ml, 1.1 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。 Oxalyl chloride was added to a solution of 2-(3-bromophenyl)acetic acid (215 mg, 1 mmol) in dichloromethane under 0 ° 〇 and under nitrogen. (0.1 ml, 1.1 mmol), the reaction mixture was stirred at room temperature for 2 hr.
2-(3，5-二甲基 -4-硝基) -1，2，3，4-四氢吡咯 [l，2-a]吡嗪 （化合物 187B)  2-(3,5-Dimethyl-4-nitro)-1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (Compound 187B)
1，2，3，4-四氢吡咯 [l，2-a]吡嗪 （244 mg, 2 mmol), 5-氟 -1,3-二甲基 -2-硝基苯（373 mg, 2.2 mmol),碳酸钾 （828 mg, 6 mmol) 溶于 5 mL N，N-二甲基甲酰胺中，反应液在 150 °C搅拌 48 h后， 反应液用水洗， 乙酸乙酯萃取， 无水硫酸钠干燥， 真空旋干溶剂， 柱层析得产物 80 mg， 收率 15%  1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (244 mg, 2 mmol), 5-fluoro-1,3-dimethyl-2-nitrobenzene (373 mg, 2.2 Methyl acetate (828 mg, 6 mmol) was dissolved in 5 mL of N,N-dimethylformamide. After stirring at 150 ° C for 48 h, the reaction mixture was washed with water and ethyl acetate. Dry over sodium sulfate, spin dry the solvent in vacuo, column chromatography to give product 80 mg, yield 15%
4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(lH))-2，6-二甲基苯胺 （化合物 187C)  4-(3,4-Dihydropyrrole [l,2-a]pyrazine-2(lH))-2,6-dimethylaniline (Compound 187C)
2-(3，5-二甲基 -4-硝基) -1，2，3，4-四氢吡咯 [l，2-a]吡嗪 （80 mg, 0.3 mmol), 连二亚硫酸钠 (522 mg, 3 mmol)溶于 5 mL 甲醇和 1 mL水中， 在 90 °C下反应 lh， 过滤， 真空旋干得产 物 （50 mg，69% yield)。  2-(3,5-Dimethyl-4-nitro)-1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (80 mg, 0.3 mmol), sodium dithionite (522 The mg, 3 mmol) was dissolved in 5 mL of methanol and 1 mL of water, and then reacted at 90 ° C for 1 h, filtered and evaporated to dryness to give the product (50 mg, 69% yield).
2-(3-溴苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺 （化合物 187) 2-(3-Bromophenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)B Amide (compound 187)
4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(lH))-2，6-二甲基苯胺 （50 mg, 0.21mmol), 碳酸钾 （87 mg, 0.63 mmol) 溶于 5 mL 四氢呋喃中，然后将 2-(3-溴苯基)乙酰氯 （60 mg， 0.252 mmol) 溶 于 5 mL 四氢呋喃中慢慢滴加到反应液中， 在室温下反应 16h 小时， 反应液用水洗， 乙 酸乙酯萃取， 无水硫酸钠干燥， 真空旋干溶剂， 柱层析得产物 15 mg, 收率 16%。 MS: 438 (M+H+)。 iHNMR (CDC13, 400 MHz): a 7.56 (s, 1H), 7.46-7.48 (m， 1H), 7.33-7.35 (m， 2H), 6.63 (s,2H), 6.58 (s, 1H), 6.50 (s, 1H), 6.16 (t, J = 2.4, 1H), 5.94 (s, 1H), 4.37 (s, 2H), 4.06 (t, J = 5.4， 2H), 3.73 (s， 2H), 3.59 (t， J= 5.4, 2H), 2.10 (s， 6H)。 4-(3,4-Dihydropyrrole[l,2-a]pyrazine-2(lH))-2,6-dimethylaniline (50 mg, 0.21 mmol), potassium carbonate (87 mg, 0.63 mmol Dissolved in 5 mL of tetrahydrofuran, then 2-(3-bromophenyl)acetyl chloride (60 mg, 0.252 mmol) was dissolved in 5 mL of tetrahydrofuran and slowly added dropwise to the reaction solution, and reacted at room temperature for 16 h. The reaction solution was washed with water, ethyl acetate and dried over anhydrous sodium sulfate. MS: 438 (M+H+). iHNMR (CDC1 3 , 400 MHz): a 7.56 (s, 1H), 7.46-7.48 (m, 1H), 7.33-7.35 (m, 2H), 6.63 (s, 2H), 6.58 (s, 1H), 6.50 (s, 1H), 6.16 (t, J = 2.4, 1H), 5.94 (s, 1H), 4.37 (s, 2H), 4.06 (t, J = 5.4, 2H), 3.73 (s, 2H), 3.59 (t, J = 5.4, 2H), 2.10 (s, 6H).
实施例一百八十八  Example one hundred eighty eight
N- 4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基) -2-间甲基苯乙酰胺的制备  Preparation of N-4-(3,4-dihydropyrrole [1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)-2-m-methylphenylacetamide
Figure imgf000140_0001
Figure imgf000140_0001
间甲基苯乙酰氯 （化合物 188A)  m-Methylphenylacetyl chloride (Compound 188A)
0 °〇和氮气保护下， 间甲基苯乙酸 （3.0 g， 20 mmol) 的二氯甲烷溶液中， 加入草酰氯 （2 ml, 22 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。  Oxyl chloride (2 ml, 22 mmol) was added to methylene phenylacetic acid (3.0 g, 20 mmol) in methylene chloride, and the mixture was stirred at room temperature for 2 hr. , used directly in the next step.
N-(4-溴 -2,6-二甲基苯基) -2-间甲基苯乙酰胺 （化合物 188B)  N-(4-bromo-2,6-dimethylphenyl)-2-m-methylphenylacetamide (Compound 188B)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 （3.64 g， 18.2 mmol) 和三乙胺 （6.4 mL， 45.5 mmol)的二氯 甲烷溶液中， 加入间甲基苯乙酰氯 （3.78 g， 20 mmol), 反应液室温搅拌 12小时后， 碳酸氢钠 终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物。 （3.8 g，65% 收率)。 N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基) -2-间甲基苯乙酰胺 （化合物 188) 本品由 N-(4-溴 -2,6-二甲基苯基) -2-间甲基苯乙酰胺 （364 mg， 1.1 mmol)和 1，2，3，4-四氢吡 咯 [l，2-a]吡嗪 （122 mg， 1 mmol) 按照化合物 115的制备方法合成， 封管中 110°C反应 3 h， 纯 化得目标化合物 (100 mg， 27%收率）。 1H NMR (400 MHz, CDC13) δ: 7.27-7.31 (m, 1H), 7.13-7.20 (m， 3H), 6.65 (s， 2H), 6.58-6.59 (m， 1H), 6.48 (s， 1H), 6.163 (t， J = 3.2, 1H), 5.92-5.93 (m， 1H)， 4.37 (s, 2H), 4.06 (t, J= 5.4， 2H), 3.74 (s, 2H), 3.59 (t, J= 5.6， 2H), 2.38 (s, 3H), 2.09 (s, 6H)。 MS: 374 (M+H+)。 0 °C, 2,6-Dimethyl-4-bromo-aniline (3.64 g, 18.2 mmol) and triethylamine (6.4 mL, 45.5 mmol) in methylene chloride (3.78 g, 20 mmol). After the reaction mixture was stirred at room temperature for 12 hrs, EtOAc EtOAc. (3.8 g, 65% yield). N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl)-2-m-methylphenylacetamide (compound) 188) This product consists of N-(4-bromo-2,6-dimethylphenyl)-2-m-methylphenylacetamide (364 mg, 1.1 mmol) and 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol) was synthesized according to the preparation method of Compound 115, and the mixture was subjected to a reaction at 110 ° C for 3 h to obtain the target compound (100 mg, 27% yield). 1H NMR (400 MHz, CDC1 3 ) δ: 7.27-7.31 (m, 1H), 7.13-7.20 (m, 3H), 6.65 (s, 2H), 6.58-6.59 (m, 1H), 6.48 (s, 1H ), 6.163 (t, J = 3.2, 1H), 5.92-5.93 (m, 1H), 4.37 (s, 2H), 4.06 (t, J= 5.4, 2H), 3.74 (s, 2H), 3.59 (t , J= 5.6, 2H), 2.38 (s, 3H), 2.09 (s, 6H). MS: 374 (M+H+).
实施例一百八十九  Example one hundred eighty nine
2- 3-甲氧基苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺的制备  2- 3-methoxyphenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl) Preparation of acetamide
Figure imgf000141_0001
Figure imgf000141_0001
2-(3-甲氧基苯基)乙酰氯 （化合物 189A)  2-(3-methoxyphenyl)acetyl chloride (compound 189A)
0 °〇和氮气保护下， 2- 3-甲氧基苯基)乙酸 3.4 g，20 mmol) 的二氯甲烷溶液中， 加入草 酰氯 （2 ml, 22 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。  Oxalyl chloride (2 ml, 22 mmol) was added to a solution of 2- methoxyphenyl)acetic acid 3.4 g (20 mmol) in m. , spin dry to obtain the product, used directly in the next reaction.
N-(4-溴 -2,6-二甲基苯基) -2-(3-甲氧基苯基)乙酰胺 （化合物 189B)  N-(4-bromo-2,6-dimethylphenyl)-2-(3-methoxyphenyl)acetamide (compound 189B)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 （3.64 g， 18.2 mmol) 和三乙胺 （6.4 mL， 45.5 mmol)的二氯 甲烷溶液中， 加入 2-(3-甲氧基苯基)乙酰氯 （3.69 g， 20 mmol), 反应液室温搅拌 12小时后， 碳酸氢钠终止溶液， 乙酸乙酯萃取，干燥过滤， 旋干，用***洗涤得到产物 (3.2 g， 51% 收率)。  0 °C, 2,6-dimethyl-4-bromo-aniline (3.64 g, 18.2 mmol) and triethylamine (6.4 mL, 45.5 mmol) in dichloromethane, 2-(3-A Ethyl phenyl) acetyl chloride (3.69 g, 20 mmol). After the reaction mixture was stirred at room temperature for 12 hrs. % yield).
2-(3-甲氧基苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺 （化合物 2-(3-methoxyphenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl Acetamide
189) 189)
本品由 N-(4-溴 -2,6-二甲基苯基) -2-(3-甲氧基苯基)乙酰胺 （381.7 mg， 1.1 mmol)禾卩 1,2,3,4- 四氢吡咯 [l，2-a]吡嗪 （122 mg， 1 mmol) 按照化合物 115的制备方法合成，封管中 110°C反应 3 h, 纯化得目标化合物 (100 mg， 15% 收率)。 1H NMR (400 MHz, CDC13) δ: 7.33-7.37 (m， 1H)， 6.98-7.00 (m, 1H), 6.95 (s, 1H), 6.89-6.91 (m, 1H), 6.76 (s, 2H), 6.58 (s, 1H), 6.63 (s, 1H), 6.20 (t, J= 3.2, 1H), 5.98 (s, 1H), 4.44 (s, 2H), 4.12 (t， J = 4.2， 2H), 3.85 (s, 3H), 3.78 (s, 2H), 3.64 (t, J = 4.2, 2H), 2.12 (s， 6H)。 MS: 390 (M+H+)。 This product consists of N-(4-bromo-2,6-dimethylphenyl)-2-(3-methoxyphenyl)acetamide (381.7 mg, 1.1 mmol) and 1,2,3,4 - Tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol) was synthesized according to the preparation method of compound 115, and reacted at 110 ° C for 3 h in a sealed tube to purify the target compound (100 mg, 15% yield) ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.33-7.37 (m, 1H), 6.98-7.00 (m, 1H), 6.95 (s, 1H), 6.89-6.91 (m, 1H), 6.76 (s, 2H ), 6.58 (s, 1H), 6.63 (s, 1H), 6.20 (t, J= 3.2, 1H), 5.98 (s, 1H), 4.44 (s, 2H), 4.12 (t, J = 4.2, 2H ), 3.85 (s, 3H), 3.78 (s, 2H), 3.64 (t, J = 4.2, 2H), 2.12 (s, 6H). MS: 390 (M+H+).
实施例一百九十  Example one hundred ninety
2-(3- (三氟甲基)苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺的制 备
Figure imgf000142_0001
2-(3-(Trifluoromethyl)phenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethyl Preparation of phenyl)acetamide
Figure imgf000142_0001
2-(3- (三氟甲基)苯基)乙酰氯 （化合物 190A)  2-(3-(trifluoromethyl)phenyl)acetyl chloride (compound 190A)
0 °〇和氮气保护下， 2-(3- (三氟甲基)苯基)乙酸 （4.1 g, 20 mmol) 的二氯甲烷溶液中， 加 入草酰氯 （2 ml, 22 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。  Oxalyl chloride (2 ml, 22 mmol) was added to a solution of 2-(3-(trifluoromethyl)phenyl)acetic acid (4.1 g, 20 mmol) in m. After stirring at room temperature for 2 hours, it was spun dry to give the product, which was used directly for the next reaction.
N-(4-溴 -2,6-二甲基苯基) -2-(3- (三氟甲基)苯基)乙酰胺 （化合物 190B)  N-(4-Bromo-2,6-dimethylphenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (Compound 190B)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 （3.64 g， 18.2 mmol) 和三乙胺 （6.4 mL， 45.5 mmol)的二氯 甲烷溶液中，加入 2-(3- (三氟甲基)苯基)乙酰氯 （4.45 g， 20 mmol),反应液室温搅拌 12小时后， 碳酸氢钠终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物。 （3.2 g，51% 收 率)。  0 °C, 2,6-Dimethyl-4-bromo-aniline (3.64 g, 18.2 mmol) and triethylamine (6.4 mL, 45.5 mmol) in dichloromethane, 2-(3-( Trifluoromethyl)phenyl)acetyl chloride (4.45 g, 20 mmol). After the reaction mixture was stirred at room temperature for 12 hrs, then the mixture was evaporated and evaporated. (3.2 g, 51% yield).
2-(3- (三氟甲基)苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺（化合 物 190)  2-(3-(Trifluoromethyl)phenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethyl Phenyl phenyl) acetamide (compound 190)
本品由 N-(4-溴 -2,6-二甲基苯基) -2-(3- (三氟甲基)苯基）乙酰胺 （462 mg， 1.1 mmol)和 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 （122 mg， 1 mmol) 按照化合物 115的制备方法合成，封管中 110°C 反应 3 h纯化得目标化合物 (50 mg， 10% 收率）。 1H NMR (400 MHz, CDC13) δ: 7.69 (s， 1H)， 7.62-7.64 (m， 2H), 7.53-7.57 (m， 1H), 6.66 (s, 2H), 6.60-6.61 (m， 1H), 6.49 (s, 1H), 6.18 (t， J= 5.2, 1H), 5.95-5.96 (m， 1H), 4.40 (s， 2H), 4.07-4.16 (m， 2H), 3.85 (s， 2H), 3.61-3.63 (m， 2H), 2.12 (s， 6H)。 MS: 428 (M+H+)。 This product consists of N-(4-bromo-2,6-dimethylphenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (462 mg, 1.1 mmol) and 1,2,3 , 4-tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol) was synthesized according to the preparation method of compound 115, and purified in a sealed tube at 110 ° C for 3 h to obtain the target compound (50 mg, 10%. rate). 1H NMR (400 MHz, CDC1 3 ) δ: 7.69 (s, 1H), 7.62-7.64 (m, 2H), 7.53-7.57 (m, 1H), 6.66 (s, 2H), 6.60-6.61 (m, 1H) ), 6.49 (s, 1H), 6.18 (t, J= 5.2, 1H), 5.95-5.96 (m, 1H), 4.40 (s, 2H), 4.07-4.16 (m, 2H), 3.85 (s, 2H) ), 3.61-3.63 (m, 2H), 2.12 (s, 6H). MS: 428 (M+H+).
实施例一百九 ^一  Example one hundred nine ^ one
2-(3，5-二氟苯基 -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺的制备  2-(3,5-Difluorophenyl-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylphenyl Preparation of acetamide
Figure imgf000142_0002
Figure imgf000142_0002
2-(3，5-二氟苯基)乙酰氯 （化合物 191A)  2-(3,5-difluorophenyl)acetyl chloride (Compound 191A)
0 °〇和氮气保护下， 2-(3，5-二氟苯基)乙酸 （3.5 g， 20 mmol) 的二氯甲烷溶液中， 加入草 酰氯 （2 ml, 22 mmol), 反应液室温搅拌 2小时后， 旋干得到产物， 直接用于下一步反应。  Ochalyl chloride (2 ml, 22 mmol) was added to a solution of 2-(3,5-difluorophenyl)acetic acid (3.5 g, 20 mmol) in dichloromethane (EtOAc). After 2 hours, the product was obtained by spin-drying and used directly for the next reaction.
N-(4-溴 -2,6-二甲基苯基) -2-(3，5-二氟苯基)乙酰胺 （化合物 191B)  N-(4-bromo-2,6-dimethylphenyl)-2-(3,5-difluorophenyl)acetamide (Compound 191B)
0 °C， 2， 6，-二甲基 -4-溴 -苯胺 （3.64 g， 18.2 mmol) 和三乙胺 （6.4 mL， 45.5 mmol)的二氯 甲烷溶液中， 加入 2-C3，5-二氟苯基)乙酰氯 （3.81 g，20 mmol)， 反应液室温搅拌 12小时后， 碳 酸氢钠终止溶液， 乙酸乙酯萃取， 干燥过滤， 旋干， 用***洗涤得到产物。 （3.2 g， 51% 收 率)。 0 °C, 2,6-Dimethyl-4-bromo-aniline (3.64 g, 18.2 mmol) and triethylamine (6.4 mL, 45.5 mmol) of dichloro To the methane solution, 2-C3,5-difluorophenyl)acetyl chloride (3.81 g, 20 mmol) was added. After the reaction mixture was stirred at room temperature for 12 hrs, sodium bicarbonate was evaporated, ethyl acetate was extracted, dried, filtered and dried. Washed with diethyl ether to give the product. (3.2 g, 51% yield).
2-(3，5-二氟苯基) -N-(4-(3，4-二氢吡咯 [1，2-α]吡嗪 -2(iH))-2，6-二甲基苯基)乙酰胺 （化合物 2-(3,5-difluorophenyl)-N-(4-(3,4-dihydropyrrole[1,2-α]pyrazine-2(iH))-2,6-dimethylbenzene Acetamide
191 ) 191)
本品由 N-(4-溴 -2,6-二甲基苯基) -2-(3，5-二氟苯基)乙酰胺 （390 mg， 1.1 mmol)和 1，2，3，4-四 氢吡咯 [l，2-a]吡嗪 （122 mg， 1 mmol), 按照化合物 115的制备方法合成， 于封管中 110°C反应 3 h, 纯化得目标化合物 （50 mg， 13% 收率）。 1H NMR (400 MHz, CDC13) δ: 6.95-6.97 (m, 2H), 6.76-6.81 (m， 1H)， 6.64 (s, 2H), 6.58-6.59 (m， 1H)， 6.55 (s, 1H)， 6.18-6.20 (m， 1H)， 5.95-5.96 (m， 1H), 4.40 (s， 2H), 4.09 (t， J = 5.6， 2H), 3.76 (s， 2H), 3.63 (t, J = 4.2, 2H), 2.14 (s， 6H)。 MS: 396 (M+H+)。 This product consists of N-(4-bromo-2,6-dimethylphenyl)-2-(3,5-difluorophenyl)acetamide (390 mg, 1.1 mmol) and 1,2,3,4 - tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol), which was synthesized according to the preparation method of compound 115, and reacted at 110 ° C for 3 h in a sealed tube to purify the target compound (50 mg, 13%) Yield). 1H NMR (400 MHz, CDC1 3 ) δ: 6.95-6.97 (m, 2H), 6.76-6.81 (m, 1H), 6.64 (s, 2H), 6.58-6.59 (m, 1H), 6.55 (s, 1H ), 6.18-6.20 (m, 1H), 5.95-5.96 (m, 1H), 4.40 (s, 2H), 4.09 (t, J = 5.6, 2H), 3.76 (s, 2H), 3.63 (t, J = 4.2, 2H), 2.14 (s, 6H). MS: 396 (M+H+).
实施例一百九十二  Example one hundred ninety two
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯基) -2-(2，5- (二甲基)苯基)乙酰胺（化 合物 192) 的制备
Figure imgf000143_0001
N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-2-(2,5- ( Preparation of dimethyl)phenyl)acetamide (Compound 192)
Figure imgf000143_0001
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 （122 mg， 1 mmol ) 禾卩 N-(4-溴 -2,6-二甲基 苯) -3-(2，5- (二甲基)苯基)乙酰胺 （346mg， 1 mmol) 按照化合物 120的制备方法合成， 纯化 得到目标化合物 ( HOmg, 收率 26%)。 MS: 388 [M+H]+。 1腿 MR (400MHz， DMSO) δ: 9. \5 (s， 1Η)， 7.12 (s，lH)， 7.05 (d， 1H, J=8Hz)， 6.95 (d， 1H, J=8Hz)， 6.72(s, 2H), 6.65(s，lH)， 6.00(t， 1H, J=3.6Hz), 5.84(s， 1H), 4.33(s, 2H), 4.02(t,2H, J=5.2Hz), 3.61-3.59(m,4H),2.28(s, 3H), 2.25(s, 3H), 2.09 (s, 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)- 3-(2,5-(Dimethyl)phenyl)acetamide (346 mg, 1 mmol) was synthesized according to the procedure for the preparation of compound 120 to afford the title compound ( HOmg, yield 26%). MS: 388 [M+H]+. 1 leg MR (400MHz, DMSO) δ: 9. \5 (s, 1Η), 7.12 (s,lH), 7.05 (d, 1H, J=8Hz), 6.95 (d, 1H, J=8Hz), 6.72 (s, 2H), 6.65(s,lH), 6.00(t, 1H, J=3.6Hz), 5.84(s, 1H), 4.33(s, 2H), 4.02(t,2H, J=5.2Hz) , 3.61-3.59 (m, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 2.09 (s, 6H).
实施例一百九十三  Example one hundred ninety three
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯基) -2-(3，4-二甲氧基苯基）乙酰胺 (化合物 193 ) 的制备
Figure imgf000143_0002
N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-2-(3,4-di Preparation of methoxyphenyl)acetamide (compound 193)
Figure imgf000143_0002
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪（122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(3， 4- (二甲氧基)苯基)乙酰胺 （378mg， 1 mmol) 按照化合物 120的制备方法合成， 得到目标化 合物 ( l lOmg, 收率 26%)。 MS: 420 [M+H]+. ^MR (400MHz, DMSO) δ: 9.17 ( s， 1H)， 6.99 (s, 1H), 6.92-6.85 (m, 2H), 6.71 (s, 2H), 6.65 (s, 1H), 5.60 (t, 1H, J=3.6Hz), 5.83 (s, 1H), 5.77 (s, 1H), 4.32 (s， 2H), 4.01 (t， 2H, J=5.2Hz), 3.75 (s,3H), 3.74 (s， 3H), 3.60 (t,2H, J=5.2Hz), 3.51 (s,2H) 2.04 (s，6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3 -(3,4-(Dimethoxy)phenyl)acetamide (378 mg, 1 mmol) was synthesized according to the preparation method of compound 120 to obtain target Compound ( l lOmg, yield 26%). MS: 420 [M+H]+. ^MR (400MHz, DMSO) δ: 9.17 ( s, 1H), 6.99 (s, 1H), 6.92-6.85 (m, 2H), 6.71 (s, 2H), 6.65 (s, 1H), 5.60 (t, 1H, J=3.6Hz), 5.83 (s, 1H), 5.77 (s, 1H), 4.32 (s, 2H), 4.01 (t, 2H, J=5.2Hz) , 3.75 (s, 3H), 3.74 (s, 3H), 3.60 (t, 2H, J = 5.2 Hz), 3.51 (s, 2H) 2.04 (s, 6H).
实施例一百九十四  Example one hundred ninety four
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯) -3-(2，4，6- (三甲基)苯基)丙酰胺（化 合物 194) 的制备
Figure imgf000144_0001
N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3-(2,4,6- Preparation of (trimethyl)phenyl)propanamide (compound 194)
Figure imgf000144_0001
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 卩比嗪（122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(2， 4， 6- (三甲基)苯基)丙酰胺 （360mg， 1 mmol) 按照化合物 120的制备方法合成， 纯化得到目 标化合物 ( l lOmg, 收率 27%)。 MS: 402 [M+H]+。 1腿 MR (400MHz， DMSO) δ: 9.05 (s, 1Η), 6.82 (s, 2H), 6.72 (s, 2H), 6.65-6.64 (m, 1H), 6.00(t, 1H, J=3.2 Hz), 5.84 (s, 1H), 4.32 (s, 2H), 4.01 (t， 2H, J= 5.2 Hz), 3.66 (s, 2H), 3.60 (t,2H, J=5.2 Hz), 2.28 (s, 6H)， 2.21 (s, 3H), 2.11 (s, 6H)。 This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyridazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)- 3-(2,4,6-(Trimethyl)phenyl)propanamide (360 mg, 1 mmol) was synthesized according to the procedure of Compound 120 to give the title compound (l lOmg, yield 27%). MS: 402 [M+H]+. 1 leg MR (400MHz, DMSO) δ: 9.05 (s, 1Η), 6.82 (s, 2H), 6.72 (s, 2H), 6.65-6.64 (m, 1H), 6.00(t, 1H, J=3.2 Hz ), 5.84 (s, 1H), 4.32 (s, 2H), 4.01 (t, 2H, J = 5.2 Hz), 3.66 (s, 2H), 3.60 (t, 2H, J = 5.2 Hz), 2.28 (s , 6H), 2.21 (s, 3H), 2.11 (s, 6H).
实施例一百九十五  Example one hundred ninety five
3-(4-氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(lH)-yl)-2，6-二甲基苯)乙酰胺 （化合物 195 ) 的制备
Figure imgf000144_0002
3-(4-fluorophenyl)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(lH)-yl)-2,6-dimethylphenyl) Preparation of amide (compound 195)
Figure imgf000144_0002
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪（70 mg， 0.55mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(2， 4， 5-三氟苯)乙酰胺 （140 mg， 0.5 mmol) 按照化合物 120的制备方法合成， 纯化得到目标化 合物 ( 80 mg，收率 38%) MS: 414 [M+H]+. 1HNMR (400MHz， CDC13) δ: 7.26 (s, 1H), 6.73 (m， 3H), 6.68 (s， 1H), 6.20 (m， 1H), 5.98 (m， 1H), 5.95 (s， 1H), 4.40 (s， 2H), 4.13(t, 2H， J= 6.0 Hz), 3.82 (s， 2H), 3.63 (t， 2H, J= 5.6Hz)， 2.18 (s， 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (70 mg, 0.55 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3 -(2,4,5-trifluorobenzene)acetamide (140 mg, 0.5 mmol) was synthesized according to the preparation of compound 120 to give the title compound (80 mg, yield 38%) MS: 414 [M+H] + . 1HNMR (400MHz, CDC1 3 ) δ: 7.26 (s, 1H), 6.73 (m, 3H), 6.68 (s, 1H), 6.20 (m, 1H), 5.98 (m, 1H), 5.95 (s, 1H), 4.40 (s, 2H), 4.13(t, 2H, J= 6.0 Hz), 3.82 (s, 2H), 3.63 (t, 2H, J= 5.6Hz), 2.18 (s, 6H).
实施例一百九十六  Example one hundred ninety six
3-(4-氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(lH)-yl)-2，6-二甲基苯)乙酰胺 （化合物 196) 的制备
Figure imgf000145_0001
3-(4-fluorophenyl)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(lH)-yl)-2,6-dimethylphenyl) Preparation of amide (compound 196)
Figure imgf000145_0001
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪（70 mg， 0.55mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(2， 3， 4， 5， 6-六氟苯)乙酰胺 （210 mg， 0.5 mmol) 按照化合物 120的制备方法合成， 纯化得到目 标化合物（60 mg，收率 25%)。 MS: 450 [M+H]+. 1HNMR (400MHz， CDC13) δ: 7.26 (s, 1H), 6.73 (m, 3H), 6.68 (s, 1H), 6.20 (m, 1H), 5.98 (m, 1H), 5.95 (s, 1H), 4.40 (s, 2H), 4.13(t, 2H， J= 6.0 Hz), 3.82 (s， 2H), 3.63 (t， 2H, J= 5.6Hz)， 2.18 (s， 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (70 mg, 0.55 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3 -(2,3,4,5,6-hexafluorobenzene)acetamide (210 mg, 0.5 mmol) was synthesized according to the preparation of compound 120 to afford the title compound (60 mg, yield 25%). MS: 450 [M+H]+. 1HNMR (400MHz, CDC1 3 ) δ: 7.26 (s, 1H), 6.73 (m, 3H), 6.68 (s, 1H), 6.20 (m, 1H), 5.98 (m , 1H), 5.95 (s, 1H), 4.40 (s, 2H), 4.13(t, 2H, J= 6.0 Hz), 3.82 (s, 2H), 3.63 (t, 2H, J= 5.6Hz), 2.18 (s, 6H).
实施例一百九十七  Example one hundred ninety seven
3-(4-氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(lH)-yl)-2，6-二甲基苯)丙酰胺 （化合物 197) 的制备
Figure imgf000145_0002
3-(4-fluorophenyl)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(lH)-yl)-2,6-dimethylphenyl)propane Preparation of amide (compound 197)
Figure imgf000145_0002
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 ( 70 mg， 1.1 eq) 和 N-(4-溴 -2,6-二甲基苯) -3-(4- 氟苯)丙酰胺（ 180mg， 0.5 mmol),按照化合物 120的制备方法合成，纯化得到目标化合物（ 100 mg， 收率 50%)。 MS: 392 [M+H]+. 1HNMR (400MHz， CDC13) δ: 7.26 (s, 1H), 7.22 (dd， 1H，J尸 8.4, J2= 2.8 Hz), 7.08 (t， 1H, J= 7.2 Hz), 6.64 (s, 2H), 6.59 (m， 1H), 6.48 (s, 1H), 6.17 (m， 1H), 5.96 (m， 1H)， 4.38 (s, 2H), 4.08 (t, 2H， J= 5.6 Hz), 3.65 (t, 2H, J= 5.6 Hz), 3.06 (t, 2H, J= 7.2Hz), 2.68 (t 2H, J= 7.2Hz), 2.06 (s， 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (70 mg, 1.1 eq) and N-(4-bromo-2,6-dimethylphenyl)-3 -(4-Fluorophenyl)propanamide (180 mg, 0.5 mmol) was synthesized according to the procedure of Compound 120 to afford the title compound (100 mg, yield 50%). MS: 392 [M+H]+. 1HNMR (400MHz, CDC1 3 ) δ: 7.26 (s, 1H), 7.22 (dd, 1H, J 8.4, J2 = 2.8 Hz), 7.08 (t, 1H, J= 7.2 Hz), 6.64 (s, 2H), 6.59 (m, 1H), 6.48 (s, 1H), 6.17 (m, 1H), 5.96 (m, 1H), 4.38 (s, 2H), 4.08 (t, 2H, J= 5.6 Hz), 3.65 (t, 2H, J= 5.6 Hz), 3.06 (t, 2H, J= 7.2Hz), 2.68 (t 2H, J= 7.2Hz), 2.06 (s, 6H).
实施例一百九十八  Example one hundred ninety eight
3-(3-氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯)丙酰胺 （化合物 198 ) 的制备  3-(3-fluorophenyl)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)propane Preparation of amide (compound 198)
Figure imgf000145_0003
Figure imgf000145_0003
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 ( 70 mg， 1.1 eq) 和 N-(4-溴 -2,6-二甲基苯) -3-(3- 氟苯)丙酰胺 （ 180mg， 0.5 mmol)按照化合物 120的制备方法合成，纯化得到目标化合物（ 100 mg，收率 50%)。 MS: 392 [M+H]+. 1HNMR (400MHz， CDC13) δ: 7.20 (s， 1H), 7.18-6.56 (m， 7H), 6.17 (m， 1H), 5.96 (m， 1H), 4.37 (s， 2H), 4.07 (t， 2H，J= 5.6 Hz), 3.65 (t， 2H, J= 5.6 Hz), 3.06 (t， 2H: J= 7.2Hz), 2.93 (t， 2H, J= 7.2Hz), 2.06 (s, 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (70 mg, 1.1 eq) and N-(4-bromo-2,6-dimethylphenyl)-3 -(3-Fluorophenyl)propanamide (180 mg, 0.5 mmol) was synthesized according to the preparation of Compound 120 to afford the title compound (100 mg, yield 50%). MS: 392 [M+H]+. 1HNMR (400MHz, CDC1 3 ) δ: 7.20 (s, 1H), 7.18-6.56 (m, 7H), 6.17 (m, 1H), 5.96 (m, 1H), 4.37 (s, 2H), 4.07 (t, 2H, J = 5.6 Hz), 3.65 (t, 2H, J = 5.6 Hz), 3.06 (t, 2H : J = 7.2 Hz), 2.93 (t, 2H, J = 7.2 Hz), 2.06 (s, 6H).
实施例一百九十九  Example one hundred ninety nine
3-(2-氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(lH)-yl)-2，6-二甲基苯)丙酰胺 （化合物 199) 的制备
Figure imgf000146_0001
3-(2-fluorophenyl)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(lH)-yl)-2,6-dimethylphenyl)propane Preparation of amide (compound 199)
Figure imgf000146_0001
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 (70 mg, 1.1 eq) 和 N-(4-溴 -2,6-二甲基苯) -3-(2- 氟苯)丙酰胺 （ 180mg， 0.5 mmol)按照化合物 120的制备方法合成，纯化得到目标化合物（ 100 mg,收率 50%)。 MS: 392 [M+H]+. 1HNMR (400MHz， CDC13) δ: 7.30 (s， 1H), 7.22 (t， 1H, J= 8.8 Hz), 7.06 (t， 1H, J= 8.0 Hz), 6.65-6.53 (m， 4H)， 6.17 (m， 1H), 5.95 (s， 1H), 4.39 (s， 2H), 4.0 l(t, 2H， J= 5.6 Hz), 3.62 (t， 2H, J= 5.6 Hz), 3.13 (t, 2H, J= 7.2Hz), 2.74 (t， 2H, J= 7.2Hz), 2.06 (s， 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (70 mg, 1.1 eq) and N-(4-bromo-2,6-dimethylphenyl)-3 -(2-Fluorophenyl)propanamide (180 mg, 0.5 mmol) was synthesized according to the preparation of Compound 120 to afford the title compound (100 mg, yield 50%). MS: 392 [M + H] + 1HNMR (400MHz, CDC1 3) δ:. 7.30 (s, 1H), 7.22 (t, 1H, J = 8.8 Hz), 7.06 (t, 1H, J = 8.0 Hz), 6.65-6.53 (m, 4H), 6.17 (m, 1H), 5.95 (s, 1H), 4.39 (s, 2H), 4.0 l(t, 2H, J= 5.6 Hz), 3.62 (t, 2H, J = 5.6 Hz), 3.13 (t, 2H, J = 7.2 Hz), 2.74 (t, 2H, J = 7.2 Hz), 2.06 (s, 6H).
实施例二百  Embodiment two hundred
3-(4-氯苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯)丙酰胺 （化合物 200) 的制备
Figure imgf000146_0002
3-(4-chlorophenyl)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)propane Preparation of amide (compound 200)
Figure imgf000146_0002
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 (70 mg, 1.1 eq) 和 N-(4-溴 -2,6-二甲基苯) -3-(4- 氯苯)丙酰胺 （ 190mg， 0.5 mmol)按照化合物 120的制备方法合成，纯化得到目标化合物（ 100 mg,收率 48%)。 MS: 408 [M+H]+. 1HNMR (400MHz， CDC13) δ: 7.23 (s， 1H), 7.20 (t， 1H, J尸 8.4 Hz), 6.62 (s, 2H), 6.59 (m, 1H), 6.45 (s, 1H), 6.18 (m, 1H), 5.96 (m, 1H), 4.38 (s, 2H), 4.08 (t, 2H， J= 5.6 Hz), 3.65 (t， 2H, J= 5.6 Hz), 3.06 (t， 2H, J= 7.2Hz), 2.68 (t， 2H, J= 7.2Hz), 2.06 (s, 6H). This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (70 mg, 1.1 eq) and N-(4-bromo-2,6-dimethylphenyl)-3 -(4-Chlorobenzene)propanamide (190 mg, 0.5 mmol) was synthesized according to the procedure of Compound 120 to afford the title compound (100 mg, yield 48%). MS: 408 [M+H] + . 1HNMR (400MHz, CDC1 3 ) δ: 7.23 (s, 1H), 7.20 (t, 1H, J 8.4 Hz), 6.62 (s, 2H), 6.59 (m, 1H ), 6.45 (s, 1H), 6.18 (m, 1H), 5.96 (m, 1H), 4.38 (s, 2H), 4.08 (t, 2H, J = 5.6 Hz), 3.65 (t, 2H, J= 5.6 Hz), 3.06 (t, 2H, J= 7.2Hz), 2.68 (t, 2H, J= 7.2Hz), 2.06 (s, 6H).
实施例二百零一  Embodiment two hundred and one
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1 氢） -基) -2,6-二甲基苯基) -3- (4-溴苯基） 丙酰胺的 制备  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-(4-bromo) Preparation of phenyl) propionamide
Figure imgf000146_0003
Figure imgf000146_0003
N- (4-溴 -2， 6-二甲基苯基） 甲酰胺 （化合物 201A) 在冰水浴下， 甲酸 （1.5 mL) 和乙酸酐 （2 mL) 搅拌 1小时， 滴加 4-溴 -2， 6-二甲基苯 胺 （2 g， lO mmol) 的二氯甲烷（20 mL)溶液。 室温下继续搅拌 1小时， 分别用饱和碳酸氢 钠，饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干溶剂，得白色针状晶体（1.9 g，收率 95%)。 N-(4-bromo-2,6-dimethylphenyl)carboxamide (Compound 201A) Under ice-water bath, formic acid (1.5 mL) and acetic anhydride (2 mL) were stirred for 1 hour, then added dropwise 4-bromo-2,6-dimethylaniline (2 g, 10 mmol) dichloromethane (20 mL) Solution. The mixture was stirred at room temperature for 1 hour, washed with saturated sodium hydrogen sulfate and brine, dried over anhydrous sodium sulfate.
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基)甲酰胺 （化合物 201B ) 三 (；二亚苄基丙酮)二钯（170 mg，0.18 mmol)和 2-二环己基磷 -2，4，6-三异丙基联苯（85 mg， 0.18 mmol)在甲苯 ( 5 mL) 中搅拌 15分钟， 分别加入 1，2，3，4-四氢吡咯 [l，2-a]吡嗪（265 mg， 2.2mmol), 化合物 201A (400 mg， 1.8 mmol) 和叔丁醇钾 （0.59 g， 5.2 mmol)。 在封管中加 热至 120°C反应 12小时。 硅藻土过滤， 旋干溶剂， 石油醚 /乙酸乙酯 （4/1 ) 分离纯化得化合 物 201B ( 140 mg, 收率 30%) 。  N-(4-(3,4-Dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)carboxamide (Compound 201B) III (; Dibenzylideneacetone) dipalladium (170 mg, 0.18 mmol) and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (85 mg, 0.18 mmol) in toluene (5 mL) After stirring for 15 minutes, 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (265 mg, 2.2 mmol), compound 201A (400 mg, 1.8 mmol) and potassium t-butoxide ( 0.59 g, 5.2 mmol). The reaction was heated to 120 ° C for 12 hours in a sealed tube. The mixture was filtered through Celite, EtOAc (EtOAc) (EtOAc)
4- ( 3， 4-二氢吡咯 [1， 2-a]吡嗪 -2 ( 1氢） -基） -2， 6-二甲基苯胺 （化合物 201 C) 氢氧化钾（300 mg， 5.2 mmol)加入到化合物 201B ( 150 mg， 0.52 mmol)的乙醇（5 mL) 溶液中， 加热至回流反应 48小时。 冷却至室温， 加入二氯甲烷和水， 有机相用饱和食盐水洗 涤， 无水硫酸钠干燥， 过滤旋干， 石油醚 /乙酸乙酯 （6/1 ) 分离纯化得化合物 201C ( 75 mg, 收率 60%) 。  4-(3,4-Dihydropyrrole[1,2-a]pyrazine-2(1H)-yl)-2,6-dimethylaniline (Compound 201 C) Potassium Hydroxide (300 mg, 5.2 Methyl) was added to a solution of compound 201B (150 mg, 0.52 mmol) in ethanol (5 mL). After cooling to room temperature, dichloromethane and water were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Rate 60%).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基) -3- (4-溴苯基）丙酰胺（化 合物 201 )  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-(4-bromo) Phenyl)propionamide (compound 201)
化合物 201C (25 mg, 0.1 mmol) 和三乙胺 （0.5 mL) 分别加入到 3- (4-溴苯基） 丙基 酰氯 （30 mg， 0.124 mmol) 的二氯甲烷 （5 mL) 溶液中， 继续搅拌 30分钟。 加入饱和碳酸 氢钠， 二氯甲烷萃取 （3x 10 mL ), 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤旋干， 石油醚 / 乙酸乙酯 （4/1 )分离纯化得化合物 201 (26 mg, 收率 46%) 。 1H NMR (400 MHz, DMSO) δ: 8.97 (s, 1H)， 7.47 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.69 (s, 2H), 6.64 (s, 1H)， 6.00 (s, 1H), 5.82 (s， 1H), 4.31 (s， 2H), 4.00 (t，J= 5.6 Hz, 2H), 3.58 (t，J= 5.6 Hz, 2H), 2.88 (t，J= 7.6 Hz, 2H), 2.59 (t，J= 7.6 Hz, 2H), 1.97 (s， 6H).  Compound 201C (25 mg, 0.1 mmol) and triethylamine (0.5 mL) were added to a solution of 3-(4-bromophenyl)propyl chloride (30 mg, 0.124 mmol) in dichloromethane (5 mL). Stirring was continued for 30 minutes. Add saturated sodium bicarbonate, dilute with dichloromethane (3×10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, and then evaporated to dryness, and then purified by petroleum ether / ethyl acetate (4/1) to obtain compound 201 (26 mg , yield 46%). 1H NMR (400 MHz, DMSO) δ: 8.97 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.69 (s, 2H), 6.64 ( s, 1H), 6.00 (s, 1H), 5.82 (s, 1H), 4.31 (s, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.58 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.97 (s, 6H).
实施例二百零二  Example two hundred and two
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基) -3-对甲苯基丙酰胺（化合物 202) 的制备  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-p-tolylpropane Preparation of amide (compound 202)
Figure imgf000147_0001
Figure imgf000147_0001
本品由 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 ( 122 mg, 1 mmol)和 N- (4-溴 -2.6-二甲基苯基) -3- 对甲苯基丙酰胺（414 mg， 1.2 mmol)按照化合物 115的制备方法合成， 封管中加热至 120°C 反应 12小时， 纯化得化合物 202 ( 130 mg， 收率 33%) 。 1H NMR (400 MHz, DMSO) δ: 8.96 (s, 1H)， 7.07-7.16 (m， 4H)， 6.69 (s, 2H), 6.64 (s, 1H)， 5.98-6.01 (m， 1H)， 5.83 (s, 1H)， 4.31 (s, 2H), 4.01 (t， J = 5.6 Hz, 2H), 5.85 (t， J = 5.6 Hz, 2H), 2.86 (t， J = 7.6 Hz, 2H), 2.56 (t， J = 7.6 Hz, 2H), 2.26 (s， 3H), 1.99 (s， 6H). This product consists of 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2.6-dimethylphenyl)-3- p-Tolylpropionamide (414 mg, 1.2 mmol) was synthesized according to the preparation method of Compound 115, and the mixture was heated to 120 ° C for 12 hours, and purified to give Compound 202 (130 mg, yield 33%). 1H NMR (400 MHz, DMSO) δ: 8.96 (s, 1H), 7.07-7.16 (m, 4H), 6.69 (s, 2H), 6.64 (s, 1H), 5.98-6.01 (m, 1H), 5.83 (s, 1H), 4.31 (s, 2H), 4.01 (t, J = 5.6 Hz, 2H), 5.85 (t, J = 5.6 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.26 (s, 3H), 1.99 (s, 6H).
实施例二百零三  Example two hundred and three
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1 氢） -基) -2,6-二甲基苯基) -3-对甲氧苯基丙酰胺 （化 合物 203 ) 的制备  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-p-methoxybenzene Preparation of acrylamide (compound 203)
Figure imgf000148_0001
Figure imgf000148_0001
本品由 1，2，3，4-四氢吡咯 [l，2-a]吡嗪 ( 122 mg, 1 mmol)和 N- (4-溴 -2.6-二甲基苯基) -3- 对甲氧基苯基丙酰胺 （433 mg， 1.2 mmol) 按照化合物 115的制备方法合成， 在封管中加热 至 120°C反应 12小时， 纯化得化合物 （lOO mg, 收率 30%) 。 1H NMR (400 MHz, DMSO) δ: 8.96 (s, 1H)， 7.17 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.69 (s, 2H), 6.63-6.65 (m， 1H)， 5.98-6.01 (m, 1H), 5.82-5.84 (m, 1H), 4.31 (s, 2H), 4.01 (t, J = 5.6 Hz, 2H), 3.72 (s, 3H), 3.58 (t, J = 5.6 Hz, 2H), 2.85 (t，J= 7.2 Hz, 2H), 2.55 (t，J= 7.2 Hz, 2H), 1.99 (s， 6H).  This product consists of 1,2,3,4-tetrahydropyrrole [l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2.6-dimethylphenyl)-3- Methoxyphenylpropanamide (433 mg, 1.2 mmol) was synthesized according to the preparation method of Compound 115, and the mixture was heated to 120 ° C for 12 hours in a sealed tube to obtain a compound (100 mg, yield 30%). 1H NMR (400 MHz, DMSO) δ: 8.96 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.69 (s, 2H), 6.63- 6.65 (m, 1H), 5.98-6.01 (m, 1H), 5.82-5.84 (m, 1H), 4.31 (s, 2H), 4.01 (t, J = 5.6 Hz, 2H), 3.72 (s, 3H) , 3.58 (t, J = 5.6 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 1.99 (s, 6H).
实施例二百零四  Embodiment two hundred and four
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯) -3-(4- (三氟甲基)苯基)丙酰胺 （化 合物 204) 的制备  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-3-(4-(trifluoromethyl) Preparation of phenyl)propanamide (Compound 204)
Figure imgf000148_0002
Figure imgf000148_0002
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪（122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(4- 三氟甲基)苯基)丙酰胺（399mg， 1 mmol)按照化合物 120的制备方法合成， 纯化得到目标化 合物 （60mg， 收率 14%)。 LCMS: 442 [M+H]+。 1腿 MR (400MHz， DMSO) δ: 8.99 ( s,lH) ， 7.66(d,2H, J=8.0Hz), 7.50 (d， 2H, J=8.0Hz), 6.99 (s,2H), 6.65-6.64 (m，lH)， 6.00 (t， 1H, J=2.8Hz), 5.83 (t, 1H， J=1.2Hz), 4.31 (s,2H), 4.01 (t, 2H, J=5.2Hz), 3.59 (t,2H, J=5.2Hz), 3.01 (t, 2H, J=7.2Hz), 2.65 (t， 2H, J=7.2Hz), 1.94 (s， 6H)。 实施例二百零五 This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3 -(4-Trifluoromethyl)phenyl)propanamide (399 mg, 1 mmol) was synthesized according to the procedure of Compound 120 to afford the title compound (60 mg, yield 14%). LCMS: 442 [M+H]+. 1 leg MR (400MHz, DMSO) δ: 8.99 ( s,lH) , 7.66 (d,2H, J=8.0Hz), 7.50 (d, 2H, J=8.0Hz), 6.99 (s,2H), 6.65- 6.64 (m,lH), 6.00 (t, 1H, J=2.8Hz), 5.83 (t, 1H, J=1.2Hz), 4.31 (s,2H), 4.01 (t, 2H, J=5.2Hz), 3.59 (t, 2H, J = 5.2 Hz), 3.01 (t, 2H, J = 7.2 Hz), 2.65 (t, 2H, J = 7.2 Hz), 1.94 (s, 6H). Example two hundred and five
3-(2，4-二氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2,6-二甲基苯)丙酰胺 （化合物 205 ) 的制备  3-(2,4-difluorobenzene)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethyl Preparation of phenyl)propanamide (compound 205)
Figure imgf000149_0001
Figure imgf000149_0001
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 卩比嗪 (122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(2，4- 二氟苯)丙酰胺 (367mg， 1 mmol)按照化合物 120的制备方法合成，纯化得到目标化合物（65mg， 收率 16%)。 LCMS: 410 [M+H]+。 1腿 MR (400MHz， DMSO) δ: 9.02(s, 1H), 7.40-7.34 (m， 1H)， 7.23 -7.18 (m， 1H)， 7.05-7.00 (m， 1H)， 6.65-6.64 (m， 1H)， 6.00 (t， 1H， J=2.8Hz), 5.83 (s, 1H)， 4.31(s,2H), 4.01(t，2H， J=5.6Hz), 3.59(t, 2H, J=5.6Hz), 2.9 l(t, 2H, J=7.2Hz), 2.60(t,2H, J=7.2Hz), 1.97(s, 6H)。 This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyridazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)- 3-(2,4-Difluorobenzene)propanamide (367 mg, 1 mmol) was obtained according LCMS: 410 [M+H]+. 1 leg MR (400MHz, DMSO) δ: 9.02(s, 1H), 7.40-7.34 (m, 1H), 7.23 -7.18 (m, 1H), 7.05-7.00 (m, 1H), 6.65-6.64 (m, 1H), 6.00 (t, 1H, J=2.8Hz), 5.83 (s, 1H), 4.31(s,2H), 4.01(t,2H, J=5.6Hz), 3.59(t, 2H, J=5.6 Hz), 2.9 l(t, 2H, J=7.2Hz), 2.60(t, 2H, J=7.2Hz), 1.97(s, 6H).
实施例二百零六  Example two hundred and six
3-(3，4-二氟苯) -N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2(1H)-基) -2，6-二甲基苯)丙酰胺 （化合物 206) 的制备  3-(3,4-difluorobenzene)-N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethyl Preparation of phenyl)propanamide (compound 206)
Figure imgf000149_0002
Figure imgf000149_0002
本品由 1，2，3，4-四氢吡咯并 [l，2-a] 吡嗪 (122 mg， 1 mmol)和 N-(4-溴 -2,6-二甲基苯) -3-(3，4- 二氟苯)丙酰胺 （367mg， 1 mmol) 按照化合物 120 的制备方法合成， 纯化得到目标化合物 ( 60mg， 收率 15%)。 LCMS: 410 [M+H]+. ^MR (400MHz, DMSO) δ: 8.99 (s, 1H), 7.38-7.31 (m， 2H), 7.11-7.09 (m， 1H)， 6.70 (s,2H), 6.65-6.64 (m，lH)， 6.0 (t， J=3.2Hz), 6.84 (s, 1H)， 5.77(s, 1H), 4.32 (s， 2H), 4.01 (t， 2H, J= 5.2Hz)， 3.59 (t， 2H, J=5.6Hz), 2.91 (t， 2H, J=7.2Hz), 2.61 (t， 2H, J=7.2Hz), 1.97(s,6H This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (122 mg, 1 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3 -(3,4-Difluorobenzene)propanamide (367 mg, 1 mmol) was synthesized according to the procedure of Compound 120 to afford the title compound (60 mg, yield 15%). LCMS: 410 [M+H] + . ^MR (400MHz, DMSO) δ: 8.99 (s, 1H), 7.38-7.31 (m, 2H), 7.11-7.09 (m, 1H), 6.70 (s, 2H) , 6.65-6.64 (m,lH), 6.0 (t, J=3.2Hz), 6.84 (s, 1H), 5.77(s, 1H), 4.32 (s, 2H), 4.01 (t, 2H, J= 5.2 Hz), 3.59 (t, 2H, J=5.6Hz), 2.91 (t, 2H, J=7.2Hz), 2.61 (t, 2H, J=7.2Hz), 1.97(s,6H
实施例二百零七  Example two hundred and seven
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基) -3- (2， 4-二氯苯基） 丙酰 胺的制备
Figure imgf000150_0001
N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-(2, 4 -Dichlorophenyl) Preparation of propionamide
Figure imgf000150_0001
3- (2， 4-二氯苯基） 丙基酰氯 （化合物 207A)  3-(2,4-dichlorophenyl) propyl acyl chloride (Compound 207A)
草酰氯 (21 L， 0.124 mmol) 滴加到 3- (2， 4-二氯苯基) 丙酸 (27 mg, 0.124 mmol) 的二氯甲烷 （3 mL) 溶液中， 并加入两滴 DMF， 室温下继续搅拌 30分钟， 旋干除去过量的 草酰氯和二氯甲烷得粗产物化合物 207A (30 mg, 收率 99%) 。  Oxalyl chloride (21 L, 0.124 mmol) was added dropwise to a solution of 3-(2,4-dichlorophenyl)propanoic acid (27 mg, 0.124 mmol) in dichloromethane (3 mL). Stirring was continued for 30 minutes at room temperature, and excess oxalyl chloride and dichloromethane were evaporated to give crude compound 207A (30 mg, yield 99%).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基) -3- (2， 4-二氯苯基） 丙酰 胺 （化合物 207)  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-(2, 4 -dichlorophenyl)propionamide (compound 207)
4- (3， 4-二氢吡咯 [1， 2-a]吡嗪 -2 ( 1氢） -基） -2， 6-二甲基苯胺 （25 mg， 0.1 mmol) 和三乙胺 （0.5 mL) 分别加入到化合物 207A (30 mg, 0.124 mmol) 的二氯甲烷 （5 mL) 溶 液中， 继续搅拌 30分钟。 加入饱和碳酸氢钠， 二氯甲烷萃取 GxlO mL), 饱和食盐水洗涤， 无水硫酸钠干燥，过滤旋干，石油醚 /乙酸乙酯（4/1 )分离纯化得化合物（15 mg， 收率 33%)。 1H NMR (400 MHz, DMSO) δ: 9.03 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.35-7.40 (m, 2H), 6.70 (s, 2H), 6.64-6.65 (m， 1H), 5.95-6.01 (m， 1H), 5.80-5.84 (m， 1H), 4.31 (s， 2H), 4.00 (t， J= 5.4 Hz, 2H): 3.59 (t，J= 5.6 Hz, 2H), 2.99 (t，J= 7.6 Hz, 2H), 2.62 (t，J= 7.6 Hz, 2H), 1.99 (s， 6H). 4-(3,4-Dihydropyrrole[1,2-a]pyrazine-2(1H)-yl)-2,6-dimethylaniline (25 mg, 0.1 mmol) and triethylamine (0.5 mL) were added to a solution of compound 207A (30 mg, 0.124 mmol) in dichloromethane (5 mL) and stirring was continued for 30 min. Add saturated sodium bicarbonate, dilute dichloromethane to extract GxlO mL), wash with saturated brine, dry over anhydrous sodium sulfate, and then filtered and evaporated to dryness with petroleum ether / ethyl acetate (4/1). 33%). 1H NMR (400 MHz, DMSO) δ: 9.03 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.35-7.40 (m, 2H), 6.70 (s, 2H), 6.64-6.65 (m , 1H), 5.95-6.01 (m, 1H), 5.80-5.84 (m, 1H), 4.31 (s, 2H), 4.00 (t, J = 5.4 Hz, 2H) : 3.59 (t, J = 5.6 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.99 (s, 6H).
实施例二百零八  Embodiment two hundred and eight
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基) -3- (3,5-二氯苯基）丙酰胺 (化合物 208) 的制备  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-(3,5 -Dichlorophenyl)propanamide (Compound 208) Preparation
Figure imgf000150_0002
Figure imgf000150_0002
3- (3， 5-二氯苯基） 丙基酰氯 （化合物 208A)  3-(3,5-Dichlorophenyl)propyl acyl chloride (Compound 208A)
草酰氯 (21 L， 0.124 mmol) 滴加到 3- (3， 5-二氯苯基) 丙酸 (27 mg, 0.124 mmol) 的二氯甲烷 （3 mL) 溶液中， 并加入两滴 DMF， 室温下继续搅拌 30分钟， 旋干除去过量的 草酰氯和二氯甲烷得粗产物化合物 208A (30 mg, 收率 99%) 。  Oxalyl chloride (21 L, 0.124 mmol) was added dropwise to a solution of 3-(3,5-dichlorophenyl)propanoic acid (27 mg, 0.124 mmol) in dichloromethane (3 mL). Stirring was continued for 30 minutes at room temperature, and excess oxalyl chloride and dichloromethane were evaporated to give crude compound 208A (30 mg, yield 99%).
N-(4-(3，4-二氢吡咯 [l，2-a]吡嗪 -2- ( 1氢） -基) -2,6-二甲基苯基) -3- (3,5-二氯苯基）丙酰胺 (化合物 208)  N-(4-(3,4-dihydropyrrole[l,2-a]pyrazine-2-(1H)-yl)-2,6-dimethylphenyl)-3-(3,5 -dichlorophenyl)propanamide (compound 208)
4- (3， 4-二氢吡咯 [1， 2-a]吡嗪 -2 ( 1氢） -基） -2， 6-二甲基苯胺 （25 mg， 0.1 mmol) 和三乙胺 （0.5 mL) 分别加入到化合物 208A (30 mg, 0.124 mmol) 的二氯甲烷 （5 mL) 溶 液中， 继续搅拌 30分钟。 加入饱和碳酸氢钠， 二氯甲烷萃取 GxlO mL), 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤旋干， 石油醚 /乙酸乙酯 （4/1 ) 分离纯化得化合物 208 ( 10 mg, 收率 23%)。 1H NMR (400 MHz, DMSO) δ: 9.00 (s, 1H)， 7.43 (s, 1H)， 7.34 (s, 2H), 6.69 (s, 2H), 6.64 (s, 1H), 5.99 (s， 1H), 5.83 (s， 1H), 4.31 (s， 2H), 4.00 (t， J= 5.6 Hz, 2H), 3.58 (t， J= 5.6 Hz, 2H), 2.93 (t， J= 7.2 Hz, 2H), 2.63 (t， J= 7.2 Hz, 2H), 1.96 (s， 6H). 4-(3,4-Dihydropyrrole[1,2-a]pyrazine-2(1H)-yl)-2,6-dimethylaniline (25 mg, 0.1 mmol) Triethylamine (0.5 mL) was added to a solution of compound 208A (30 mg, 0.124 mmol) in dichloromethane (5 mL). Add saturated sodium bicarbonate, dilute dichloromethane to extract GxlO mL), wash with saturated brine, dry over anhydrous sodium sulfate, and then filtered and evaporated to dryness. Rate 23%). 1H NMR (400 MHz, DMSO) δ: 9.00 (s, 1H), 7.43 (s, 1H), 7.34 (s, 2H), 6.69 (s, 2H), 6.64 (s, 1H), 5.99 (s, 1H) ), 5.83 (s, 1H), 4.31 (s, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.58 (t, J = 5.6 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H ), 2.63 (t, J = 7.2 Hz, 2H), 1.96 (s, 6H).
实施例二百零九  Example two hundred and nine
N-(4-(3，4-二氢吡咯并 [l，2-a]吡嗪 -2 ( 1H) -基) -2,6-二甲基苯基) -2-丙基戊酰胺（化合物 209) 的制备
Figure imgf000151_0001
N-(4-(3,4-dihydropyrrolo[l,2-a]pyrazine-2(1H)-yl)-2,6-dimethylphenyl)-2-propylpentanamide ( Preparation of compound 209)
Figure imgf000151_0001
本品由 1，2，3，4-四氢吡咯并 [l，2-a]吡嗪（ 112 mg， 0.92 mmol)和 N- (4-溴 -2,6-二甲基苯基） -2-丙基戊酰胺 （300 mg, 0.92 mmol) 按照化合物 120的制备方法合成， 纯化得化合物 209， 为白色固体（20 mg, 6%收率）。 MS: 368.3 (M+H+).1H NMR (400 MHz, DMSO- 6) δ: 8.99 (s, 1H): 6.72 (s,lH), 6.65 (s， 1H)， 5.99-6.01 (t, Ji = 3.2 Hz, J2= 2.8 Hz, 1H), 5.83 (s, 1H), 4.33 (s, 2H), 4.00-4.03 (t， Ji = 5.2 Hz, J2= 5.6 Hz, 2H), 3.59-3.62 (t， Ji = 5.2 Hz, J2= 5.6 Hz, 2H), 2.50-2.51 (m， 1H), 2.10 (s， 6H)， 1.54-1.59 (m， 2H), 1.31-1.38 (m， 6H)， 0.89-0.93 (t, Ji = 7.2 Hz, J2= 6.8 Hz, 6H). 实施例二百一" h This product consists of 1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine (112 mg, 0.92 mmol) and N-(4-bromo-2,6-dimethylphenyl)- 2-Pentyl pentamide (300 mg, 0.92 mmol) was synthesized according to the procedure of compound 120 to afford compound 209 as a white solid (20 mg, 6% yield). MS: 368.3 (M+H + ).1H NMR (400 MHz, DMSO-6) δ: 8.99 (s, 1H) : 6.72 (s,lH), 6.65 (s, 1H), 5.99-6.01 (t, Ji = 3.2 Hz, J 2 = 2.8 Hz, 1H), 5.83 (s, 1H), 4.33 (s, 2H), 4.00-4.03 (t, Ji = 5.2 Hz, J 2 = 5.6 Hz, 2H), 3.59-3.62 (t, Ji = 5.2 Hz, J 2 = 5.6 Hz, 2H), 2.50-2.51 (m, 1H), 2.10 (s, 6H), 1.54-1.59 (m, 2H), 1.31-1.38 (m, 6H) , 0.89-0.93 (t, Ji = 7.2 Hz, J 2 = 6.8 Hz, 6H). Example two hundred" h
N-(4-(6- -3，4-二氢吡咯 [l，2-a]哌嗪 -2(1H)-基) -2，6-二甲基苯基) -3，3-二甲基丁酰胺的制备 N -(4-(6- -3,4-dihydropyrrole[l,2-a]piperazine-2(1H)-yl)-2,6-dimethylphenyl)-3,3-di Preparation of methylbutyric acid
2-(1Η-吡咯 -1-基)乙胺 （化合物 210A)  2-(1Η-pyrrole-1-yl)ethylamine (Compound 210A)
将吡咯（13.42 g， 200 mmol), 2-氯乙胺盐酸盐 (23.2 g， 200 mmol) 和四丁基酸酸氢胺 （700 mg, 2 mmol)溶于乙腈 （300 mL)， 反应回流 48小时。溶剂减压蒸干，加入乙酸乙酯 (600 mL)， 饱和的碳酸钠溶液洗涤， 无水硫酸钠干燥， 旋干， 粗产品柱色谱分离 （二氯甲烷 /甲醇 =10:1) 得到目标产物 (15 g， 收率 68%)。  Pyrrole (13.42 g, 200 mmol), 2-chloroethylamine hydrochloride (23.2 g, 200 mmol) and tetrabutylhydroperamine (700 mg, 2 mmol) were dissolved in acetonitrile (300 mL). 48 hours. The solvent was evaporated to dryness, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated (15 g, yield 68%).
1，2，3，4-四氢吡咯 [l，2-a]哌嗪 （化合物 210B) 将 2-(1Η-吡咯 -1-基)乙胺 (15 g， 135 mmol), 37% 甲醛水溶液 (4.05 g， 135 mmol)溶入乙醇1,2,3,4-tetrahydropyrrole [l,2-a] piperazine (compound 210B) 2-(1Η-pyrrol-1-yl)ethylamine (15 g, 135 mmol), 37% aqueous formaldehyde (4.05 g, 135 mmol) was dissolved in ethanol
(300 mL)中， 加入三氟乙酸 （7.5 mL) ， 该反应液在 50°C搅拌半个小时， 随后在冷却至室温下 搅拌 4小时。 溶剂减压蒸干， 残留物中加入乙酸乙酯， 用饱和的碳酸氢钠溶液洗涤， 无水硫 酸钠干燥， 旋干后， 产品直接用于下一步反应。 (300 mL), trifluoroacetic acid (7.5 mL) was added, and the mixture was stirred at 50 ° C for half an hour, then stirred at room temperature for 4 hours. The solvent was evaporated to dryness under reduced pressure. ethyl acetate was evaporated.
1，2，3，4-四氢吡咯 [l，2-a]-Boc-哌嗪 （化合物 210C)  1,2,3,4-tetrahydropyrrole [l,2-a]-Boc-piperazine (Compound 210C)
将上一步的粗产品和 N，N-二异丙基乙胺 (21 g， 162 mmol)溶于二氯甲烷 (400 mL), 冷却至 0°C， 缓慢加入二碳酸二叔丁酯 （29.1 g， 135 mmol) ， 该反应液室温下搅拌 16小时。 加入饱 和的碳酸钠溶液， 分离有机相， 有机相分别用水， 饱和的食盐水洗涤， 无水硫酸钠干燥， 旋 干后柱色谱分离 （石油醚 /乙酸乙酯 =10: 1)得到目标产物 （10 g， 两步收率 30%)。  The crude product from the previous step and N,N-diisopropylethylamine (21 g, 162 mmol) were dissolved in dichloromethane (400 mL), cooled to 0 ° C, and di-tert-butyl dicarbonate (29.1) was slowly added. g, 135 mmol), the reaction was stirred at room temperature for 16 h. The saturated sodium carbonate solution was added, and the organic phase was separated, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and then evaporated to dryness (ethyl ether / ethyl acetate = 10:1) 10 g, 30% yield in two steps).
四 -丁基 6-氯 -3,4-二氢吡咯 [l，2-a]哌嗪 -2(1H)-碳酸甲酯 （化合物 210D)  Tetrabutyl 6-chloro-3,4-dihydropyrrole [l,2-a] piperazine-2(1H)-methyl carbonate (compound 210D)
在 -40°C和氮气保护下，将 N-氯丁酰胺 （239 mg， 1.8 mmol) 加入到 四 -丁基 6-氯 -3,4-二氢 吡咯 [l，2-a]哌嗪 -2C1H)-碳酸甲酯 C400 mg， 1.8 mmol) 二氯甲烷（；40 mL) 溶液中，该反应再次温 度下继续反应 2小时。 反应结束后， 加入水 （20 mL) ， 恢复至室温， 分离出有机相， 有机相 用饱和的食盐水洗涤， 无水硫酸钠干燥， 旋干， 柱色谱分离 （石油醚 /乙酸乙酯 =20: 1)得到目 标产物 210D (300 mg，收率 64%)。  Add N-chlorobutyramide (239 mg, 1.8 mmol) to tetra-butyl 6-chloro-3,4-dihydropyrrole [l,2-a] piperazine at -40 ° C under nitrogen. 2C1H)-methyl carbonate C400 mg, 1.8 mmol) methylene chloride (40 mL). After the reaction was completed, water (20 mL) was added, and the mixture was evaporated to room temperature. The organic phase was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. : 1) The target product 210D (300 mg, yield 64%) was obtained.
6-氯 -1，2，3，4-四氢吡咯 [l，2-a]哌嗪 （化合物 210E)  6-Chloro-1,2,3,4-tetrahydropyrrole [l,2-a]piperazine (Compound 210E)
将四 -丁基 6-氯 -3,4-二氢吡咯 [l，2-a]哌嗪 -2(1H)-碳酸甲酯 （300 mg， 1.167 mmol) 和 三氟 乙酸 /二氯甲烷 （1/3， 10 mL) ， 在室温下搅拌 2小时， 用饱和的碳酸氢钠溶液淬灭， 用二氯 甲烷萃取， 有机相用饱和的食盐水洗涤， 旋干后直接用于下一步反应。  Tetrabutyl 6-chloro-3,4-dihydropyrrole [l,2-a] piperazine-2(1H)-methyl carbonate (300 mg, 1.167 mmol) and trifluoroacetic acid / dichloromethane ( 1/3, 10 mL), stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and washed with brine, dried and evaporated.
N-(4-(6-氯 -3,4-二氢吡咯 [l，2-a]哌嗪 -2(1H)-基) -2,6-二甲基苯基) -3,3-二甲基丁酰胺（化合物 N- (4-(6-Chloro-3,4-dihydropyrrole[l,2-a]piperazine-2(1H)-yl)-2,6-dimethylphenyl)-3,3- Dimethylbutyramide
210) 210)
本品由 6-氯 -1，2，3，4-四氢吡咯 [l，2-a]哌嗪 (78.5 mg， 0.5 mmol)和 N-(4-溴 -2,6-二甲基苯 基) -3,3-二甲基丁酰胺 （150 mg， 0.5 mmol) 按照化合物 120的制备方法合成， 纯化得到目标产 物 210 (20 mg， 15 % yield)。 MS: 374.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 8.91 (s, 1H)， 6.74(s, 2H), 6.40(d，J=3.6 Hz， 1H)， 5.93(d, J=3.6 Hz, 1H), 4.31 (s, 2H), 3.88 (t, J= 5.6 Hz, 2H), 2.82 (t，J= 5.2 Hz, 2H), 2.17 (s, 2H), 2.10 (s, 6H)， 1.05 (s, 9H). This product consists of 6-chloro-1,2,3,4-tetrahydropyrrole [l,2-a] piperazine (78.5 mg, 0.5 mmol) and N-(4-bromo-2,6-dimethylbenzene -3,3-Dimethylbutanamide (150 mg, 0.5 mmol) was synthesized according to the procedure for the preparation of compound 120 to afford the desired product 210 (20 mg, 15% yield). MS: 374.2 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 8.91 (s, 1H), 6.74 (s, 2H), 6.40 (d, J = 3.6 Hz, 1H), 5.93 (d, J=3.6 Hz, 1H), 4.31 (s, 2H), 3.88 (t, J= 5.6 Hz, 2H), 2.82 (t, J= 5.2 Hz, 2H), 2.17 (s, 2H), 2.10 (s, 6H), 1.05 (s, 9H).
实施例二百一" I ^一  Example two hundred one" I ^ one
N-(4-(2-溴 -6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基) -2-丙级戊酰胺 （化合物 211 ) 的制备
Figure imgf000153_0001
N-(4-(2-Bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-propanthene Preparation of amide (compound 211)
Figure imgf000153_0001
在室温下，将 4-(2-溴 -6,7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯胺 （337 mg， 1 mmol) 和三乙胺 C202 mg， 2 mmol)在二氯甲烷 CIO mL)中搅拌半个小时， 然后将 2-丙基戊酰氯 (；162 mg， 1 mmol) 逐滴的加入到上述溶液中， 室温下搅拌过夜。 用水 （10 mL)淬灭， 分离有机相， 有 机相用饱和的食盐水洗涤，无水硫酸钠干燥，旋干，粗产品用乙腈重结晶得到目标产物 211(200 mg， 收率 43%)。 MS: 465.2 (M+H+). 1H NMR (400 MHz, DMSO) δ: 8.99 (s, 1H), 7.02 ( s， 1H)， 6.69 ( s，2H)， 4.17 ( s，，2H)， 3.54 (t, J=5.6 Hz, 2H), 2.81 (s, 2H), 2.51 (s, 1H),2.09 ((s, 6H), 1.55 (m， 2H), 1.33(m, 6H)， 0.90 (t， J=6.8 Hz, 6H). 4-(2-Bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (337 mg, 1 mmol) at room temperature And triethylamine C202 mg, 2 mmol) in dichloromethane (10 mL), stirred for half an hour, then 2-propylpentanoyl chloride (; 162 mg, 1 mmol) was added dropwise to the above solution at room temperature Stir under overnight. The organic phase was separated with EtOAc (EtOAc) (EtOAc) MS: 465.2 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 8.99 (s, 1H), 7.02 (s, 1H), 6.69 (s, 2H), 4.17 (s, 2H), 3.54 (t, J=5.6 Hz, 2H), 2.81 (s, 2H), 2.51 (s, 1H), 2.09 ((s, 6H), 1.55 (m, 2H), 1.33(m, 6H), 0.90 (t , J=6.8 Hz, 6H).
实施例二百一" h二  Embodiment two hundred one" h two
N-(4-(2-溴 -6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基) -2-(2-氧吡咯啉 -1-基)丁酰 胺 （化合物 212
Figure imgf000153_0002
N-(4-(2-Bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-2-(2- Oxypyrrolidin-1-yl)butanamide (Compound 212
Figure imgf000153_0002
在室温下，将 4-(2-溴 -6,7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲苯胺 （337 mg， 1 mmol), 2-0氧吡咯啉 -1-基)丁酸 （171 mg， 1 mmol), 1H-苯并*** -1-基氧三吡咯烷基六氟磷酸盐 (1.04 g， 2 mmol ) 禾 B N，N-二异丙基乙胺 （260 mg， 2 mmol)在 N，N-二甲基乙酰胺 (10 mL)中搅拌过 夜。 反应结束后， 加入乙酸乙酯和水， 分离有机相， 用饱和的食盐水洗涤， 旋干后， 反相柱 色谱分离得到目标产物 212 (200mg, 收率 40 % )。 MS: 490.0 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.10 (s, 1H), 7.02 ( s， 1H)， 6.70 ( s，2H)， 4.56 ( dd， J=3.6 Hz， 1H)， 4.18 (s, 2H), 3.56 (t， J=5.6 Hz, 4H)， 3.36 (m， 1H), 2.11 (t， J=4.8Hz, 2H) 2.31 (m， 2H), 2.29 ((s， 6H)， 2.05 (m， 3H)， 1.93 (m， 1H),0.87 (t， J=7.2Hz, 11H). 4-(2-Bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (337 mg, 1 mmol) at room temperature , 2-0 oxapyrroline-1-yl)butyric acid (171 mg, 1 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.04 g, 2 mmol) N-Diisopropylethylamine (260 mg, 2 mmol) was stirred in N,N-dimethylacetamide (10 mL) overnight. After completion of the reaction, ethyl acetate and water were added, and the organic phase was separated, washed with saturated aqueous sodium chloride, and evaporated to dryness. MS: 490.0 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 9.10 (s, 1H), 7.02 (s, 1H), 6.70 (s, 2H), 4.56 ( dd, J = 3.6 Hz, 1H), 4.18 (s, 2H), 3.56 (t, J=5.6 Hz, 4H), 3.36 (m, 1H), 2.11 (t, J=4.8Hz, 2H) 2.31 (m, 2H), 2.29 (( s, 6H), 2.05 (m, 3H), 1.93 (m, 1H), 0.87 (t, J=7.2Hz, 11H).
实施例二百一" h三  Embodiment two hundred one" h three
2-(l- (氨基甲基)环己基) -N-(4-(2-溴 -6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基)乙 酰胺的制备
Figure imgf000154_0001
2-(l-(Aminomethyl)cyclohexyl)-N-(4-(2-bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2, Preparation of 6-dimethylphenyl)acetamide
Figure imgf000154_0001
四 -丁基 ((1-(2-((4-(2-溴 -6，7-二氢 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯基)氨基) -2-乙氧)环己 基)甲基)碳酸甲酯 （化合物 213A)  Tetra-butyl ((1-(2-((4-(2-)-bromo-6,7-dihydro[3,2-c]pyridine-5(4H)-yl)), 2,6-dimethyl Phenyl)amino)-2-ethoxyxo)cyclohexyl)methyl)methyl carbonate (compound 213A)
在室温下， 将 4-(2-溴 -6,7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲苯胺 （337 mg， 1 mmol), 2-(1-( ((四 -顶级碳酸)氨基)甲基)环己基)乙酸 (271 mg， 1 mmol), 1H-苯并*** -1-基氧三吡咯浣 基六氟磷酸盐 (1.04 g， 2 mmol ) 禾 B N，N-二异丙基乙胺 （260 mg， 2 mmol)在 N，N-二甲基乙酰胺 (10 mL)中搅拌过夜。 反应结束后， 加入乙酸乙酯和水， 分离有机相， 用饱和的食盐水洗涤， 旋干后， 反相柱色谱分离得到目标产物 （200mg，3 % 收率）。  4-(2-Bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylaniline (337 mg, 1 mmol) at room temperature , 2-(1-( ((Tetra-p-Carboxy))amino)methyl)cyclohexyl)acetic acid (271 mg, 1 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.04 g, 2 mmol) EtOAc (EtOAc, EtOAc) After the reaction was completed, ethyl acetate and water were added, and the organic layer was separated, washed with saturated aqueous sodium chloride and evaporated to dryness.
2-(1- (氨基甲基)环己基) -N-(4-(2-溴 -6,7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基)乙 酰胺 （化合物 213 )  2-(1-(Aminomethyl)cyclohexyl)-N-(4-(2-bromo-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2, 6-dimethylphenyl)acetamide (compound 213)
室温下， 四 -丁基 ((1-(2-((4-(2-溴 -6,7-二氢 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯基)氨基) -2- 乙氧)环己基)甲基)碳酸甲酯 （200 mg， 0.33 mmol) 和三氟乙酸（2 mL) 在二氯甲烷 (10 mL) 中 搅拌 2小时旋干后，反相柱色谱分离得到目标产物 213 (50 mg， 收率 30%)。MS: 490.0 (M+H+). 1H NMR (400 MHz, DMSO) δ: 9.53 (s， 1H)， 7.96 ( s， 3H)， 7.02 ( s， 1H)， 6.72 ( s， 2H)， 4.19 ( s，， 2H), 3.56 (t, J=5.6 Hz, 2H), 2.91 (d, J=5.6 Hz, 2H) 2.81 (s， 2H), 2.51 (s， 1H),2.09 ((s， 6H)， 1.52 (m, 11H). Tetrabutyl-((1-(2-((4-(2-(2-(2-)-)-[rho]-[rho]-]-dihydro[3,2-c]pyridine-5(4H)-yl)-2,6- Methyl dimethyl phenyl)amino) -2- ethoxy) cyclohexyl)methyl) carbonate (200 mg, 0.33 mmol) and trifluoroacetic acid (2 mL) After spin-drying, reverse phase column chromatography gave the title product 213 (50 mg, yield 30%). MS: 490.0 (M+H + ). 1H NMR (400 MHz, DMSO) δ: 9.53 (s, 1H), 7.96 (s, 3H), 7.02 (s, 1H), 6.72 (s, 2H), 4.19 ( s,, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.91 (d, J=5.6 Hz, 2H) 2.81 (s, 2H), 2.51 (s, 1H), 2.09 ((s, 6H) , 1.52 (m, 11H).
实施例二百一" h五  Embodiment two hundred one" h five
N- (4，7-氟 -1，2，3，4-四氢 -1，4-亚甲基异喹啉 -2 ( 1H) -基） -2，6-甲基苯基） -3,3-二甲基丁酰 胺的制备 N-(4,7-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-methylphenyl)-3 , 3-dimethylbutyramide preparation
Figure imgf000155_0001
Figure imgf000155_0001
2- (4-氟苯基） 乙酸乙酯 （化合物 215A)  2-(4-Fluorophenyl)acetate (Compound 215A)
4-氟苯乙酸 （ 15.4 g， 100 mmol) 溶于乙醇 （1 L)， 加入浓硫酸 （20 mL)， 滴加完毕后， 回流搅拌过夜。 将溶剂旋干后加入水（lOO mL), 乙酸乙酯萃取 （3 x400 mL) ， 合并有机相， 分别用饱和的碳酸氢钠和食盐水洗， 用无水硫酸钠干燥两个小时， 有机相加压蒸干后得到无 色的目标化合物 （18g， 98% 收率）。  4-Fluorophenylacetic acid (15. 4 g, 100 mmol) was dissolved in ethanol (1 L), and concentrated sulfuric acid (20 mL) was added. The solvent was spun dry, water (100 mL), ethyl acetate (3×400 mL), and the combined organic phases were washed with saturated sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate for two hours. After evaporation to dryness, the title compound (18 g, 98% yield) was obtained.
2—二甲基- (4-氟苯基） 丁二酸 （化合物 215B)  2-dimethyl-(4-fluorophenyl)succinic acid (compound 215B)
2- (4-氟苯基）乙酸乙酯（6.1 g，33.5mmol)溶于干燥的四氢呋喃（1.5 L)后，冷却至 -78 V , 滴加六甲基二硅基胺基钠 （20.1mL， 40.2 mmol), 并保持温度稳定在 -78 搅拌一个小时， 然 后加入溴乙酸乙酯 （4.5mL， 40.2 mmol )。 该反应液在 -78 搅拌一个小时， 然后再在 -40 搅拌两个小时。 反应结束后， 加入（70 ml醋酸的***溶液）， 过滤， 滤液旋干， 柱色谱分离， 用石油醚： 乙酸乙酯 =3: 1纯化得到目标化合物为淡黄色油状产物 （6.5g，86%两步收率）。  Ethyl 2-(4-fluorophenyl)acetate (6.1 g, 33.5 mmol) was dissolved in dry tetrahydrofuran (1.5 L), cooled to -78 V, and hexamethyldisilazide sodium (20.1 mL) was added dropwise. , 40.2 mmol), and kept the temperature stable at -78 for one hour, then ethyl bromoacetate (4.5 mL, 40.2 mmol). The reaction was stirred at -78 for one hour and then at -40 for two hours. After the reaction was completed, (70 ml of aq. EtOAc, EtOAc, EtOAc (EtOAc) Two-step yield).
2- (4-氟苯基） 丁二酸 （化合物 215C )  2-(4-fluorophenyl) succinic acid (compound 215C)
2-二甲基- ( 3-氟苯基） 丁二酸 （6.5g， 24.2 mmol) 溶于水 （1 L)， 加入氢氧化钾 （4.8 g， 120.8 mmol in 50 mL water)后回流 20个小时。 冷却至室温， 用稀盐酸 （1 M) 中和至 PH=6 后有大量沉淀析出， 过滤得到粗产物， 正空干燥后得到白色固体 （6.0 g，99%)。  2-Dimethyl-(3-fluorophenyl)succinic acid (6.5g, 24.2 mmol) dissolved in water (1 L), added with potassium hydroxide (4.8 g, 120.8 mmol in 50 mL water) and refluxed 20 hour. After cooling to room temperature, a large amount of precipitate was precipitated after neutralization with dilute hydrochloric acid (1 M) to pH = 6 and filtered to give a crude product which was obtained as a white solid (6.0 g, 99%).
3- (4-氟苯基） 丁二酸酐 （化合物 215D)  3-(4-fluorophenyl) succinic anhydride (compound 215D)
将 2- ( 3-氟苯基） 丁二酸 （3.5g)， 乙酰氯 （25mL) 和氯化亚砜 （1.3 mL) 的混合物加热 回流三个小时。 将溶剂旋干后得到粗产物， 该化合物不经纯化， 直接用于下步反应。  A mixture of 2-(3-fluorophenyl)succinic acid (3.5 g), acetyl chloride (25 mL) and thionyl chloride (1.3 mL) was refluxed for three hours. The solvent was spun dry to give a crude material which was used in the next step without purification.
5-氟 -3-氧代 -2,3-二氢 -1H-茚小甲酸 （化合物 215E)  5-fluoro-3-oxo-2,3-dihydro-1H-indole carboxylic acid (Compound 215E)
3- ( 3-氟苯基）丁二酸酐 （3.2 g， 40 mmol)溶于 1，2-二氯乙烷 （30 mL)后， 于 0 °C滴加 至三氯化铝 （11 g， 82.5 mmol) 的 1， 2-二氯乙烷 （25 mL) 溶液中， 滴加完毕后在室温继续 搅拌 1小时， 之后在 0 °C加入水 （lOO mL) 淬灭， 乙酸乙酯萃取 （3 X 120 mL) ， 有机相减 压蒸干得到化合物 215E， 为浅黄色油状产物 （50 g， 73% 两步收率） 。 3-(3-Fluorophenyl) succinic anhydride (3.2 g, 40 mmol) was dissolved in 1,2-dichloroethane (30 mL) and added dropwise to aluminum trichloride (11 g) at 0 °C. 82.5 mmol) of 1,2-dichloroethane (25 mL) was added and stirred at room temperature for 1 hour, then added with water (100 mL) at 0 ° C, and extracted with ethyl acetate (3) X 120 mL), organic phase subtraction Compressed to dryness to give compound 215 s as a pale yellow oil (50 g, 73% yield).
5-氟 -3-氧代 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 215F)  5-fluoro-3-oxo-2,3-dihydro-1H-indole methyl formate (Compound 215F)
化合物 215E (500 mg, 2.4 mmol) 溶于 20mL甲醇后， 滴加 0.5 mL浓硫酸， 反应液加热 回流 5小时之后， 旋干溶剂， 所得混合物使用石油醚： 乙酸乙酯 =10:1纯化得到化合物 215F 为淡黄色油状产物 （500mg，67%两步收率）。  After compound 215E (500 mg, 2.4 mmol) was dissolved in 20 mL of methanol, 0.5 mL of concentrated sulfuric acid was added dropwise, and the reaction mixture was heated to reflux for 5 hr, then the solvent was evaporated to dryness. 215F is the product as a light yellow oil (500 mg, 67% yield).
5-氟 -3-肟 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 215G)  5-fluoro-3-indole-2,3-dihydro-1H-indole methyl formate (compound 215G)
盐酸羟胺 （250mg， 3.6 mmol) 和乙酸钠 （82 mg， 4.8 mmol) 溶于 15 mL水， 化合物 6-氟 -3-氧代 -2,3-二氢 -1H-茚小甲酸甲酯的制备的制备 （500mg， 2.4 mmol)及乙醇（95%， 150 mL) 缓慢滴加到上述溶液中，该反应液加热回流 3小时，旋干溶剂，加入水， 乙酸乙酯（3 X 50 mL) 萃取， 有机相用无水硫酸钠干燥， 减压旋干溶剂得到化合物为白色固体 （500mg)。  Preparation of hydroxylamine hydrochloride (250mg, 3.6mmol) and sodium acetate (82mg, 4.8mmol) in 15 mL of water, compound 6-fluoro-3-oxo-2,3-dihydro-1H-indole methyl formate Preparation (500mg, 2.4mmol) and ethanol (95%, 150mL) were slowly added dropwise to the above solution, the reaction was heated to reflux for 3 hours, the solvent was evaporated, water was added, ethyl acetate (3 X 50 mL) The organic phase was dried over anhydrous sodium sulfate.
5-氟 -3-氨基 -2,3-二氢 -1H-茚小甲酸甲酯 （化合物 215H)  5-fluoro-3-amino-2,3-dihydro-1H-indole methyl formate (compound 215H)
化合物 6-氟 -3-肟 -2,3-二氢 -1H-茚小甲酸甲酯的制备的制备 （500mg， 2.4 mmol) 溶于 150 mL甲醇后， 加入 2mL浓盐酸及 0.6 g 10%的钯碳， 在 60 psi下氢化还原 48 h。 过滤除去催化 剂， 将滤液减压旋干得到白色固体 （500mg， 85%收率）。  Preparation of the compound 6-fluoro-3-indol-2,3-dihydro-1H-indole methyl formate (500 mg, 2.4 mmol) After dissolving in 150 mL of methanol, 2 mL of concentrated hydrochloric acid and 0.6 g of 10% Palladium on carbon, hydrogenated at 60 psi for 48 h. The catalyst was removed by filtration, and the filtrate was evaporated to dryness to give a white solid (500 mg,
5-氟 -3-氨基 -2,3-二氢 -1H-茚小甲酸 （化合物 2151)  5-fluoro-3-amino-2,3-dihydro-1H-indolemic acid (compound 2151)
化合物 6-氟 -3-氨基 -2,3-二氢 -1H-茚小甲酸甲酯的制备 （55mg， 0.26 mmol) 溶于 5.0 mL 水后， 加入 4.0 mL4N浓盐酸后， 加热回流 5 h， 使用减压蒸馏旋干溶剂后， 得到化合物的盐 酸盐的粗产品，该粗产物使用乙醇 /甲基叔丁基醚重结晶得到化合物 2151为白色固体（50mg)。  Preparation of compound 6-fluoro-3-amino-2,3-dihydro-1H-indole methyl formate (55 mg, 0.26 mmol) After dissolving in 5.0 mL of water, after adding 4.0 mL of 4N concentrated hydrochloric acid, the mixture was heated to reflux for 5 h. The solvent was evaporated to dryness to give crystals crystals crystals crystals crystals crystals
7-氟 -1,2-二氢 -1,4-亚甲基异喹啉 -3(4H)-酮 （化合物 215 J)  7-Fluoro-1,2-dihydro-1,4-methyleneisoquinoline-3(4H)-one (Compound 215 J)
化合物 6-氟 -3-氨基 -2,3-二氢 -1H-茚 -1-甲酸 ( (50mg, 0.26mmol) ) 及吡啶 ( 0.04 mL, 0.512mmol)溶于 15 mL乙腈中，加入二环己基碳二亚胺（58 mg， 0.282 mmol)的乙腈（20 mL) 溶液。 反应液加热回流 l h， 不溶物（二环己基脲）使用滤纸过滤除去， 滤液减压旋干得到化 合物 215J (40 mg， 37% for four steps )。 该化合物不经纯化， 直接用于下步反应。  The compound 6-fluoro-3-amino-2,3-dihydro-1H-indole-1-carboxylic acid ((50 mg, 0.26 mmol)) and pyridine (0.04 mL, 0.512 mmol) were dissolved in 15 mL of acetonitrile. A solution of hexylcarbodiimide (58 mg, 0.282 mmol) in acetonitrile (20 mL). The reaction solution was heated to reflux for 1 h, and the insoluble material (dicyclohexylurea) was removed by filtration using a filter paper, and the filtrate was dried under reduced pressure to give compound 215J (40 mg, 37% for four steps). This compound was used in the next step without purification.
7-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉 （化合物 215K)  7-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (compound 215K)
四氢铝锂 （ 17 mg， 0.45 mmol) 溶于 50 mL四氢呋喃中， 冰水浴降温至 0 °C后， 滴加化 合物 215F (40mg, 0.23 mmol) 的四氢呋喃 （5.0 mL) 溶液， 滴加过程中保持反应液的内温不 超过 10 V。 滴加完毕后， 反应液回流 3 h。 降至室温后， 过量的四氢铝锂使用 Fieser方法除 去。 过滤除去铝盐， 滤液使用乙酸乙酯萃取（3 X 50 mL) ， 有机相减压旋干得到化合物 215K 为黄色油状， 该产物不经纯化直接用于下一步反应中 (35 mg, 79% yield)。  Lithium tetrahydrogenate (17 mg, 0.45 mmol) was dissolved in 50 mL of tetrahydrofuran. After cooling to 0 °C in ice-water bath, a solution of compound 215F (40 mg, 0.23 mmol) in tetrahydrofuran (5.0 mL) was added dropwise during the dropwise addition. The internal temperature of the reaction solution does not exceed 10 V. After the addition was completed, the reaction solution was refluxed for 3 h. After dropping to room temperature, excess lithium aluminum hydride was removed using the Fieser method. The aluminum salt was removed by filtration, and the filtrate was purified eluting with ethyl acetate (3 <RTI ID=0.0></RTI> </RTI> <RTIgt; ).
N- (4,7-氟 -1，2，3，4-四氢 -1,4-亚甲基异喹啉 -2 ( 1H) -基） -2,6-甲基苯基） -3,3-二甲基丁酰 胺 （化合物 215 ) N-(4,7-fluoro-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-2(1H)-yl)-2,6-methylphenyl)-3 ,3-dimethylbutyryl Amine (compound 215)
本品由化合物 215K (35mg, 0.43 mmol) 和 N- (4-溴代 -2,6-二甲基苯基） -3-甲基丁酰胺 ( 123 mg， 0.86mmol) 按照化合物 115的制备方法合成， 于 110°C封管反应 8 h， 纯化得目标 产物。 纯化后目标产物在甲醇 /乙酸乙酯 /石油醚中重结晶得到化合物 215为白色固体 （30mg， 37% yield) 。 MS: 381 (M+H+).1H NMR (400 MHz, CDC13) 5:7.20(d, J= 8.0， 1H), 7.01 (m， 1H)， 6.88 (m， 1H)， 6.45(s, 1H), 6.35 (s, 2H), 4.95 (s, 1H), 3.84 (d, J= 8.8 Hz, 1H), 3.66 (s, 1H), 2.45 (m， 1H), 2.25 (s, 2H)， 2.17 (s, 1H), 1.14 (m， 1H), 1.00 (s, 9H).  This product consists of compound 215K (35mg, 0.43mmol) and N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide (123 mg, 0.86mmol) according to the preparation method of compound 115 The synthesis was carried out at 110 ° C for 8 h, and the target product was purified. After purification, the title compound was crystallized from EtOAc/EtOAc (EtOAc) MS: 381 (M+H+).1H NMR (400 MHz, CDC13) 5: 7.20 (d, J = 8.0, 1H), 7.01 (m, 1H), 6.88 (m, 1H), 6.45 (s, 1H) , 6.35 (s, 2H), 4.95 (s, 1H), 3.84 (d, J = 8.8 Hz, 1H), 3.66 (s, 1H), 2.45 (m, 1H), 2.25 (s, 2H), 2.17 ( s, 1H), 1.14 (m, 1H), 1.00 (s, 9H).
实施例二百一" h六  Embodiment two hundred one" h six
N-(4-(7- -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺的制备  Preparation of N-(4-(7- -1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000157_0001
Figure imgf000157_0001
N-(3-氟苯基)肉桂酰胺 （化合物 216A)  N-(3-fluorophenyl)cinnamamide (Compound 216A)
将吡啶 （ 3.5 g， 0.045 mol)禾卩 4-二甲胺基吡啶 （0.55 g， 4.46 mmol)溶于 20 mL 的二氯甲 烷中， 降温至 0°C， 氮气保护下， 滴加肉桂酰氯 （7.43 g， 0.045 mol) 的二氯甲烷溶液 10 mL， 搅拌 15分钟后， 0°C下滴 2，4-二氟苯胺 （5.00 g， 0.045 mol) 的二氯甲烷溶液 10 mL, 10分钟 后滴加完毕， 搅拌 15分钟。 升至室温， 搅拌 4个小时。 反应完毕， 加入水， 用二氯甲烷萃取 三遍， 合并二氯甲烷层， 干燥， 粗品经石油醚 /乙酸乙酯 =10:1过柱纯化得化合物 216A为白色 固体 ( 10 g，93%收率）。  Pyridine (3.5 g, 0.045 mol) and 4-dimethylaminopyridine (0.55 g, 4.46 mmol) were dissolved in 20 mL of dichloromethane, cooled to 0 ° C, and cinnamoyl chloride was added dropwise under nitrogen. 7.43 g, 0.045 mol) of 10 mL dichloromethane solution, stir for 15 minutes, then drop 2,4-difluoroaniline (5.00 g, 0.045 mol) in 10 mL of dichloromethane solution at 0 °C, 10 minutes later After the addition is completed, stir for 15 minutes. Raise to room temperature and stir for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with methylene chloride. The methylene chloride layer was combined and dried. The crude product was purified by petroleum ether / ethyl acetate = 10:1 to afford compound 216A as white solid (10 g, 93% rate).
7-氟喹啉 -2-醇 （化合物 216B)  7-fluoroquinolin-2-ol (compound 216B)
将化合物 216A (6.00 g， 2.5 mmol)与三氯化铝 （ 10 g， 7.5 mmol) 置于封管中， 快速升温 至三氯化铝的熔融状， 并于 120°C下搅拌反应 4小时。 冷却至室温， 加入冰水， 乙酸乙酯萃 取三遍， 合并有机层， 干燥， 粗品用石油醚 /乙酸乙酯 =1 :5 过柱纯化的化合物 216B, 为褐色 固体 （7 g，75%收率）。  Compound 216A (6.00 g, 2.5 mmol) and aluminum trichloride (10 g, 7.5 mmol) were placed in a sealed tube, and the temperature was rapidly increased to a molten aluminum trichloride, and the reaction was stirred at 120 ° C for 4 hours. After cooling to room temperature, ice water was added, and the mixture was combined with EtOAc EtOAc EtOAcjjjjjjj rate).
2-氯 -7-氟喹啉 （化合物 216C)  2-chloro-7-fluoroquinoline (compound 216C)
将化合物 216B ( 1.5 g, 9.20 mmol) 和苯基膦酰二氯 （4 mL， 1.74 mmol) 置于封管中， 加 热至 140°C搅拌反应 4个小时。 降至室温， 将反应液倒入冰中， 搅拌， 乙酸乙酯萃取三遍， 合并有机层， 干燥， 旋干， 粗品用石油醚 /乙酸乙酯 =5:1 过柱纯化的化合物 216C, 为红色固 体 ( 800 mg，47%收率）。 Compound 216B (1.5 g, 9.20 mmol) and phenylphosphonic dichloride (4 mL, 1.74 mmol) were placed in a sealed tube, and the mixture was heated to 140 ° C and stirred for 4 hours. The reaction mixture was poured into ice, stirred, and extracted with ethyl acetate three times. The organic layer was combined, dried and evaporated to dryness, and the crude product was purified by petroleum ether / ethyl acetate = 5:1. Red solid Body (800 mg, 47% yield).
N-(4-(7-氟喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合物 216D)  N-(4-(7-fluoroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 216D)
将化合物 216C (400 mg， 2.21 mmol) 溶于 15 mL 乙二醇二甲醚和 15 mL水的混合溶液 中， 依次向溶液中加入 N- (2， 6-二甲基 -4- (4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 -2-基） 苯基） -3， 3-二甲基丁酰胺 （915 mg， 2.65 mmol), 碳酸钾 （3.0 g， 22.1 mmol), 双三苯基磷二 氯化钯 （78 mg， 0.11 mmol)。 氮气保护下， 反应液 80°C搅拌 2个小时， 反应完毕， 分出有机 层， 旋干， 粗品用石油醚 /乙酸乙酯 =1 :1过柱纯化得到目标化合物， 为黄色固体（400 mg， 50% 收率）。  Compound 216C (400 mg, 2.21 mmol) was dissolved in a mixture of 15 mL of ethylene glycol dimethyl ether and 15 mL of water, and N-(2,6-dimethyl-4-(4, 4, 5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,3-dimethylbutanamide (915 mg, 2.65 mmol), potassium carbonate ( 3.0 g, 22.1 mmol), bistriphenylphosphine palladium dichloride (78 mg, 0.11 mmol). Under a nitrogen atmosphere, the reaction mixture was stirred at 80 ° C for 2 hours. After completion of the reaction, the organic layer was separated, dried, and then purified eluted with petroleum ether / ethyl acetate = 1:1 to afford the title compound as a yellow solid (400 mg , 50% yield).
N-(4-(7-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲基苯基) -3， 3-二甲基丁酰胺（化合物 216) 将化合物 216D (400 mg， 1.13 mmol)溶于 10 mL 的甲醇溶液中，加入二氧化铂（40 mg)， 滴加一滴醋酸， 氢气置换反应体系三遍， 室温搅拌反应过夜。 反应完毕， 滤除催化剂， 滤液 旋干， 粗品经制备分离得到化合物 216， 为白色固体（360 mg， 90%收率）。 MS: 369.3 (M+H+)。 1H NMR (400 MHz, DMSO- 6) δ: 7.1 (m， 2H), 6.9 (m， 1H), 6.86 (m， 1H), 6.74 (d, J= 9.6 Hz, 1H): 6.3 (m， 2H), 4.39 (m， 1H), 2.77(m, 1H), 2.55 (m， 1H), 2.21 (s， 2H), 2.13 (s， 6H)， 1.88 (m， 2H), 1.06 (s， 9H). N- (4-(7-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (compound) 216) Compound 216D (400 mg, 1.13 mmol) was dissolved in 10 mL of methanol solution, platinum oxide (40 mg) was added, and a drop of acetic acid was added dropwise. The reaction system was replaced with hydrogen three times, and the reaction was stirred at room temperature overnight. After completion of the reaction, the catalyst was filtered off, the filtrate was evaporated to dryness, and the crude product was isolated to afford compound 216 as white solid (360 mg, 90% yield). MS: 369.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 7.1 (m, 2H), 6.9 (m, 1H), 6.86 (m, 1H), 6.74 (d, J = 9.6 Hz, 1H) : 6.3 (m, 2H ), 4.39 (m, 1H), 2.77 (m, 1H), 2.55 (m, 1H), 2.21 (s, 2H), 2.13 (s, 6H), 1.88 (m, 2H), 1.06 (s, 9H) .
实施例二百一" h七  Embodiment two hundred one" h seven
N-(4-(7-氟小甲基 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合 物 217) 的制备
Figure imgf000158_0001
N-(4-(7-fluorosuccinyl-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide Preparation of Compound 217)
Figure imgf000158_0001
N-(4-(7-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （200 mg，0.54 mmol)溶于 10 mL 甲醇溶液， 搅拌下， 依次加入甲醛水溶液（0.2 mL)， 氰基硼氢化钠 （102 mg, 1.62 mmol) 和一滴醋酸。 反应液回流搅拌过夜。 加入水， 用乙酸乙酯萃取三遍， 合并有 机层， 干燥， 旋干， 粗品经制备分离得目标化合物 （80 mg，39%收率）。 MS: 383.3 (M+H+)。 1H NMR (400 MHz, DMSO- 6) δ: 7.1 (m， 2H), 6.9 (m， 1H)， 6.86 (m， 1H)， 6.74 (d, J = 9.6 Hz, 1H), 6.3 (m， 2H), 4.39 (m， 1H), 2.88(m, 5H)， 2.30 (s， 2H), 2.23 (s， 6H)， 1.88 (m， 2H), 1.30 (s， 9H). 实施例二百一" h八 N-(4-(7-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) was dissolved in 10 mL of methanol, and with stirring, aqueous formaldehyde (0.2 mL), sodium cyanoborohydride (102 mg, 1.62 mmol) and one drop of acetic acid were added. The reaction was stirred at reflux overnight. Water was added, and the mixture was extracted with EtOAc EtOAc (EtOAc). MS: 383.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 7.1 (m, 2H), 6.9 (m, 1H), 6.86 (m, 1H), 6.74 (d, J = 9.6 Hz, 1H), 6.3 (m, 2H) ), 4.39 (m, 1H), 2.88 (m, 5H), 2.30 (s, 2H), 2.23 (s, 6H), 1.88 (m, 2H), 1.30 (s, 9H). Example two hundred one" h eight
N-(4-(8-氟小甲基 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺 （化合 物 218) 的制备
Figure imgf000159_0001
N-(4-(8-Fluoromethyl-1,2,3,4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide Preparation of Compound 218)
Figure imgf000159_0001
化合物 N-(4-(8-氟 -1， 2， 3， 4-四氢喹啉 -2-基) -2， 6-二甲苯基) -3， 3-二甲基丁酰胺（200 mg， 0.54 mmol) 溶于 10 mL 甲醇溶液， 搅拌下， 依次加入甲醛水溶液 （0.2 mL)， 氰基硼氢化钠 Compound N-(4-(8-fluoro-1, 2, 3, 4-tetrahydroquinolin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg , 0.54 mmol) dissolved in 10 mL of methanol solution, with stirring, add formaldehyde aqueous solution (0.2 mL), sodium cyanoborohydride
( 102 mg, 1.62 mmol) 和一滴醋酸。 反应液回流搅拌过夜。 加入水， 用乙酸乙酯萃取三遍， 合并有机层，干燥，旋干，粗品经制备分离得目标化合物（80 mg, 39%收率）。 MS: 383.3 (M+H+)。 1H NMR (400 MHz, DMSO- 6) δ: 9.09 (s, 1H), 7.01 (s, 2H), 6.91 (m, 1H), 6.81 (m, 1H), 6.67 (m, 1H), 4.12 (dd， Ji = 3.6Hz, J2 = 4.0Hz, 1H)， 2.79 (m， 4H)， 2.58 (m， 1H)， 2.21(s, 2H), 2.13 (s， 6H)， 1.77 (s, 1H)， 1.06 (s, 9H). (102 mg, 1.62 mmol) and one drop of acetic acid. The reaction was stirred at reflux overnight. Water was added, and the mixture was extracted with EtOAc EtOAc (EtOAc). MS: 383.3 (M+H + ). 1H NMR (400 MHz, DMSO-6) δ: 9.09 (s, 1H), 7.01 (s, 2H), 6.91 (m, 1H), 6.81 (m, 1H), 6.67 (m, 1H), 4.12 (dd , Ji = 3.6Hz, J 2 = 4.0Hz, 1H), 2.79 (m, 4H), 2.58 (m, 1H), 2.21(s, 2H), 2.13 (s, 6H), 1.77 (s, 1H), 1.06 (s, 9H).
实施例二百一" h九  Embodiment two hundred one" h nine
N- (2，6-二甲基 -4- (2-喹啉基） 苯基） -3,3-二甲基丁酰胺的制备
Figure imgf000159_0002
Preparation of N-(2,6-dimethyl-4-(2-quinolinyl)phenyl)-3,3-dimethylbutanamide
Figure imgf000159_0002
N- (2,6-二甲基 -4- (2-喹啉基） 苯基） -3,3-二甲基丁酰胺 （化合物 219A)  N-(2,6-Dimethyl-4-(2-quinolinyl)phenyl)-3,3-dimethylbutanamide (Compound 219A)
将 2-溴喹啉（548 mg, 2.63 mmol)溶于 12 mL 乙二醇二甲醚和 12 mL水的混合溶液中， 氮气保护下， 加入 N- (4-溴 -2,6-二甲基苯基） -3,3-二甲基叔丁基甲基酰胺 （998 mg, 2.89 mmol), 双三苯基膦二氯化钯（91 mg， 0.13 mmol)和碳酸钾（3.32 g， 24 mmol)。氮气保护下， 80°C搅拌反应 3小时。 加水， 乙酸乙酯萃取， 合并， 干燥， 经石油醚 /乙酸乙酯 =1/1过柱分离 纯化得目标产物 219A ( 862 mg, 94% 收率） MS: 347.3(M+H+). Dissolve 2-bromoquinoline (548 mg, 2.63 mmol) in a mixture of 12 mL of ethylene glycol dimethyl ether and 12 mL of water, and add N-(4-bromo-2,6-dimethyl) under nitrogen. Phenyl)-3,3-dimethyl-tert-butylmethylamide (998 mg, 2.89 mmol), bistriphenylphosphine palladium dichloride (91 mg, 0.13 mmol) and potassium carbonate (3.32 g, 24 mmol) . The reaction was stirred at 80 ° C for 3 hours under a nitrogen atmosphere. Add water, extract with ethyl acetate, combine, dry, and purify with petroleum ether / ethyl acetate = 1 / 1 to obtain the desired product 219A ( 862 mg, 94% yield) MS: 347.3 (M+H + ).
N- (2,6-二甲基 -4- (-1，2，3，4-四氢喹啉 2-基) 苯基） -3,3-二甲基丁酰胺 （化合物 219B) 将化合物 219A ( 862 mg, 2.49 mmol)溶于 10 mL甲醇溶液中， 加入一滴醋酸和二氧化铂 (57 mg, 0.25 mmol)。氢气条件下室温搅拌 3小时。滤除二氧化铂， 旋除甲醇的化合物 219B (335 mg, 38%收率）。 MS: 351.3 (M+H+).  N-(2,6-Dimethyl-4-(-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)-3,3-dimethylbutanamide (Compound 219B) 219A (862 mg, 2.49 mmol) was dissolved in 10 mL of methanol, and a drop of acetic acid and platinum dioxide (57 mg, 0.25 mmol) was added. Stir at room temperature for 3 hours under hydrogen. Compound 219B (335 mg, 38% yield) was removed by filtration of platinum dioxide. MS: 351.3 (M+H+).
N- (4- ( 1-乙基-1，2，3，4-四氢喹啉-2-基） 2，6-二甲基苯基） 3，3-二甲基丁酰胺盐酸盐（化合 物 219)  N-(4-(1-ethyl-1,2,3,4-tetrahydroquinolin-2-yl) 2,6-dimethylphenyl) 3,3-dimethylbutanamide hydrochloride (compound 219)
将化合物 219B (335 mg, 0.96 mmol)溶于 10 mL甲醇溶液中，氮气保护下，加入乙醛（85 mg, 1.92 mmol), 氰基硼氢化钠 （ 121 mg， 1.92 mmol) 和一滴醋酸。 65°C搅拌反应过夜。 加 水淬灭， 旋除甲醇， 经制备分离纯化得产物， 用盐酸***溶液酸化得其盐酸盐 （205 mg，52% 收率） 。 MS: 379.3 (M+H+).1H NMR (400 MHz, CDC13) δ: 7.73-7.77 (m， 1H), 7.42 (m， 2H), 7.33-7.42 (m， 2H) ， 7.28 (s, 2H), 4.55-4.60 (m， 1H )， 3.39-3.60 (m,2H), 2.98-3.12 (m， 2H) 2.58-2.68 (m， 1H), 2.37 (s, 3H), 2.26 (s, 6H)， 1.20-1.24 (t， Ji = 6.8 Hz, J2 = 6.0 Hz, 3H), 1.16 (s: 9H). Compound 219B (335 mg, 0.96 mmol) was dissolved in 10 mL MeOH. EtOAc (EtOAc, EtOAc, EtOAc) The reaction was stirred at 65 ° C overnight. After quenching with water, the methanol was separated, and the product was isolated and purified, and acidified with diethyl ether (ethyl acetate) to give the hydrochloride salt (205 mg, 52% yield). MS: 379.3 (M+H + ).1H NMR (400 MHz, CDC1 3 ) δ: 7.73-7.77 (m, 1H), 7.42 (m, 2H), 7.33-7.42 (m, 2H), 7.28 (s, 2H), 4.55-4.60 (m, 1H), 3.39-3.60 (m, 2H), 2.98-3.12 (m, 2H) 2.58-2.68 (m, 1H) , 2.37 (s, 3H), 2.26 (s, 6H), 1.20-1.24 (t, Ji = 6.8 Hz, J 2 = 6.0 Hz, 3H), 1.16 (s : 9H).
实施例二百二十  Embodiment two hundred twenty
N- 4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2，6-二甲基苯) -3， 3-二甲基丁酰胺的制备
Figure imgf000160_0001
Preparation of N-4-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide
Figure imgf000160_0001
(E) -2- (2-硝基乙烯基） 呋喃 （化合物 220A)  (E) -2-(2-nitrovinyl) furan (compound 220A)
呋喃 -2-甲醛 ( 6.0 g, 60.6 mmol), 硝基甲烷 ( 6.8 ml, 62.8 mmol) 和醋酸胺 ( 14.4 g, 187.8 mmol)溶于 100ml醋酸中， 80°C搅拌反应 5小时。 反应结束， 反应液降至室温， 倒入冰水中， 过滤， 得到的固体用乙醇洗涤， 得到黄色固体化合物， 进一步干燥， 得到化合物 220A ( 3.5 g， 41.2%产率）。  Furan-2-carbaldehyde (6.0 g, 60.6 mmol), nitromethane (6.8 ml, 62.8 mmol) and amine acetate (14. 4 g, 187.8 mmol) were dissolved in 100 ml of acetic acid and stirred at 80 ° C for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, and filtered, and the obtained solid was washed with ethanol to give a yellow solid compound, which was further dried to give Compound 220A (3.5 g, 41.2% yield).
2- (呋喃 -2-) 乙胺 （化合物 220B)  2-(furan-2-)ethylamine (compound 220B)
四氢铝锂 （2.7 g， 71.2 mmol) 悬浮于干燥的四氢呋喃， 降至 0°C， 慢慢加入化合物 220A ( 3.3 g, 23.7 mmol), 氮气保护下搅拌反应 30分钟， 然后升温至回流， 反应 48小时。 反应结 束， 冷却到室温， 分别加入 2.7ml水， 2.7ml 15%的氢氧化钠溶液和 8.1ml水， 过滤， 得到滤 液有机层用无水硫酸钠干燥， 减压浓縮。 粗品化合物 220B (2.3 g， 88%收率） 直接用于下一 步反应。  Lithium tetrahydrogenate (2.7 g, 71.2 mmol) was suspended in dry tetrahydrofuran, dropped to 0 ° C, and compound 220A (3.3 g, 23.7 mmol) was slowly added. The reaction was stirred under nitrogen for 30 minutes, then warmed to reflux. 48 hours. After the reaction was completed, it was cooled to room temperature, and then 2.7 ml of water, 2.7 ml of 15% sodium hydroxide solution and 8.1 ml of water were added and filtered to give a filtrate. The crude compound 220B (2.3 g, 88% yield) was used directly in the next step.
4，5，6，7-四氢呋喃 [3，2，c]吡啶 （化合物 220C)  4,5,6,7-tetrahydrofuran [3,2,c]pyridine (Compound 220C)
带温度计的三口烧瓶中加入化合物 220B ( 1.3 g， 0.01 mol)， 多聚甲醛 （390 mg， 0.013 mmol)和 100ml二氯甲烷， 回流反应 5小时。 冷却至室温， 加入 80ml 7%的盐酸 DMF溶液， 65 °C搅拌反应 5小时， 然后室温搅拌反应 12小时。 反应结束， 浓縮反应液， 加入水， 用二氯 甲烷萃取。 水层加入饱和碳酸氢钠溶液， 用异丙醇 /氯仿 =1 : 5的有机层萃取， 有机层用无水 硫酸钠干燥， 减压浓縮。 粗品化合物 220C ( 1.1 g， 76%收率） 直接用于下一步反应。  Compound 220B (1.3 g, 0.01 mol), paraformaldehyde (390 mg, 0.013 mmol) and 100 ml of dichloromethane were added to a three-necked flask equipped with a thermometer, and refluxed for 5 hours. After cooling to room temperature, 80 ml of a 7% hydrochloric acid DMF solution was added, and the reaction was stirred at 65 ° C for 5 hours, and then the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was concentrated, water was added, and extracted with dichloromethane. The aqueous layer was added with a saturated aqueous solution of sodium bicarbonate, and the organic layer was evaporated. The crude compound 220C (1.1 g, 76% yield) was used directly in the next step.
N-(4-(6，7-二氢噻吩 [3，2-c]吡啶 -5(4H)-基) -2,6-二甲基苯) -3， 3-二甲基丁酰胺（化合物 220) 本品由化合物 220C (200 mg, 1.63 mmol)和 N-(4-溴 -2， 6-二甲基苯) -3， 3-二甲基丁酰胺 (580 mg, 1.95 mmol) 按照化合物 120的制备方法合成， 纯化得到化合物 220(40 mg，7%收率)。 MS: 435.3 (M+H+). 1H NMR (400 MHz, CDC13) δ: 7.38 (s, 1H), 7.03 (s, 2H), 6.72 (m, 1H), 6.32 (s: 1H), 4.36 (s， 2H), 3.74 (m， 2H), 2.97(m, 2H), 2.33 (s， 2H), 2.10 (s， 6H)， 1.16 (m， 9H). 实施例二百二 ^一 N-(4-(6,7-Dihydrothiophene[3,2-c]pyridine-5(4H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide Compound 220) This product consists of compound 220C (200 mg, 1.63 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (580 mg, 1.95 mmol) The preparation of Compound 120 was synthesized and purified to give Compound 220 (40 mg, 7% yield). MS: 435.3 (M+H + ). 1H NMR (400 MHz, CDC1 3 ) δ: 7.38 (s, 1H), 7.03 (s, 2H), 6.72 (m, 1H), 6.32 (s : 1H), 4.36 (s, 2H), 3.74 (m, 2H), 2.97 (m, 2H), 2.33 (s, 2H), 2.10 (s, 6H), 1.16 (m, 9H). Embodiment two hundred and two
N-(4-(7-氟 -(2，3，4，5-四氢 -1H-苯并 [b]氮杂 -1- 基) -2,6-二甲基苯基 3，3-二甲基丁酰胺的制 备
Figure imgf000161_0001
N-(4-(7-fluoro-(2,3,4,5-tetrahydro-1H-benzo[b]aza-1-yl)-2,6-dimethylphenyl 3,3- Preparation of dimethylbutyramide
Figure imgf000161_0001
6-氟 -1，2，3，4-四氢 -1-萘酮 （化合物 221A)  6-fluoro-1,2,3,4-tetrahydro-1-naphthalenone (Compound 221A)
6-氨基 -1，2，3，4-四氢 -1-萘酮 （4.83 g， 30 mmol) 溶于 7.5 mL水和 7.5 mL浓盐酸中， 在 0 °C下， 将亚硝酸钠水溶液 （2.2 g， 7.5 mL, 31.8 mmol) 慢慢加入， 并保持反应液温度低于 10 °C， 反应 15 min， 将四氟硼酸钠水溶液 （4.62 g， 7.5 mL， 42 mmol) 慢慢加入， 并保持 反应液温度低于 10 °C， 反应 10 min， 过滤， 分别用 l mL冰水， 0.5 mL冰甲醇， 1 mL 冰***洗， 固体干燥， 溶于甲苯， 回流 l h， 减压旋干溶剂得到产物 （1.5 g，30% 收率)。  6-Amino-1,2,3,4-tetrahydro-1-naphthalenone (4.83 g, 30 mmol) Dissolved in 7.5 mL of water and 7.5 mL of concentrated hydrochloric acid, at 0 ° C, aqueous sodium nitrite ( 2.2 g, 7.5 mL, 31.8 mmol) slowly add, keep the temperature of the reaction below 10 °C, react for 15 min, slowly add sodium tetrafluoroborate solution (4.62 g, 7.5 mL, 42 mmol) and keep The reaction temperature was lower than 10 ° C, the reaction was carried out for 10 min, filtered, and washed with 1 mL of ice water, 0.5 mL of ice methanol, 1 mL of iced diethyl ether, dried solid, dissolved in toluene, refluxed for 1 h, (1.5 g, 30% yield).
6-氟-苯并环己酮肟 （化合物 221B )  6-fluoro-benzocyclohexanone oxime (Compound 221B)
6-氟 -1，2，3，4-四氢 -1-萘酮 (1.5 g, 9.15 mmol),乙酸钠 （903 mg， 11 mmol)和盐酸羟胺 （765 g, 11 mmol) 溶于甲醇 （30 mL) 中，升温至回流反应 1 小时，反应结束加入乙酸乙酯 （50 mL) 稀释， 然后加入 2 N氢氧化钠溶液 （13 mL) ， 减压旋干有机溶剂， 加入水 （40 mL)和乙酸 乙酯 （80 mL)， 水层在用乙酸乙酯萃取 （50 mL)， 用食盐水 （50 mL) 洗有机层， 减压旋干溶 剂得到棕色的粗产品 （1.4 g， 产率 93%)。  6-Fluoro-1,2,3,4-tetrahydro-1-naphthalenone (1.5 g, 9.15 mmol), sodium acetate (903 mg, 11 mmol) and hydroxylamine hydrochloride (765 g, 11 mmol) dissolved in methanol ( In 30 mL), warm to reflux for 1 hour, dilute with ethyl acetate (50 mL) at the end of the reaction, then add 2 N sodium hydroxide solution (13 mL), dry the organic solvent under reduced pressure, add water (40 mL) The mixture was extracted with EtOAc (EtOAc) (EtOAc) %).
7-氟 -4,5-二氢 -1H-苯并 [b]氮杂环庚烯 -2 ( 3H) -酮 （化合物 221C )  7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (compound 221C)
6-氟-苯并环己酮肟 C1.4 g， 7.78 mmol) 加入到多聚磷酸 （；30 mL) 中， 升温至 80 °C 反应 16 小时， 将反应液加入到水（50 mL) 中溶解，乙酸乙酯萃取（50 mIX3 ) ， 合并有机层干燥， 减压旋干， 乙醇重结晶得到产物 （700 mg， 产率 50% ).  6-Fluoro-benzocyclohexanone oxime C1.4 g, 7.78 mmol) was added to polyphosphoric acid (30 mL), warmed to 80 ° C for 16 hours, and the reaction solution was added to water (50 mL). Dissolved, extracted with ethyl acetate (50 mIX3), combined organic layer dried, dried under reduced pressure, and recrystallized from ethanol to give product (700 mg, yield 50%).
7-氟 -2，3，4，5-四氢 -1H-苯并 [b]氮杂 （化合物 221D)  7-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (compound 221D)
在 0 °C 下，将溶有四氢锂铝 （670 mg， 17.6 mmol) 的四氢呋喃 （30 mL) 溶液慢慢滴 加到溶有 7-氟 -4,5-二氢 -1H-苯并 [b]氮杂环庚烯 -2 ( 3H) -酮 （700 mg， 3.9 mmol) 的四氢呋喃 A solution of tetrahydrofuran (30 mL) in which lithium aluminum hydride (670 mg, 17.6 mmol) was dissolved was slowly added dropwise to dissolve in 7-fluoro-4,5-dihydro-1H-benzene at 0 °C. b] azepan-2 (3H)-one (700 mg, 3.9 mmol) in tetrahydrofuran
(20 mL) 溶液中， 滴加完毕后， 升温至回流反应 24 小时， 冷却到室温， 用 20%的氢氧 化钾溶液淬灭， 固体过滤， 有机相用无水硫酸钠干燥， 减压旋干得到无色液体 （400 mg， 产率 61%)。 (20 mL) In the solution, after the dropwise addition is completed, the mixture is heated to reflux for 24 hours, cooled to room temperature, quenched with 20% potassium hydroxide solution, filtered, and dried over anhydrous sodium sulfate. A colorless liquid (400 mg, yield 61%) was obtained.
N-(4-(7-氟 -(2，3，4，5-四氢 -1H-苯并 [b]氮杂 -1- 基) -2,6-二甲基苯基 3，3-二甲基丁酰胺（化合 物 221 ) 本品由 7-氟 -2，3，4，5-四氢 -1H-苯并 [b]氮杂 （390 mg， 2.36 mmol)和 N-(4-溴代 -2,6-二甲基苯 基） -3-甲基丁酰胺 （843 mg， 2.84 mmol) 按照化合物 120的制备方法合成， 110°C 反应 4小 时， 纯化得目标产物 （600 mg， 产率 67%)， MS: 383 (M+H+)。 iHNMR (CDC13， 400 MHz): δ 7.09-7.12 (m， 1H), 6.96-6.99 (m， 1H), 6.87-6.92 (m， 1H), 6.45 (s，lH)， 6.27 (s 2H), 3.59 (s， 2H), 2.59-2.62 (m， 2H), 2.26 (s, 2H), 2.13 (s, 6H)， 1.79-1.83 (m， 2H), 1.69 (s, 2H), 1.13 (s, 9H)。 N-(4-(7-fluoro-(2,3,4,5-tetrahydro-1H-benzo[b]aza-1-yl)-2,6-dimethylphenyl 3,3- Dimethylbutyramide (compound 221) This product consists of 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]aza (390 mg, 2.36 mmol) and N-(4-bromo-2,6-dimethyl Phenyl)-3-methylbutanamide (843 mg, 2.84 mmol) was synthesized according to the preparation method of compound 120, and reacted at 110 ° C for 4 hours to purify the title product (600 mg, yield 67%), MS: 383 ( M+H + ). iHNMR (CDC1 3 , 400 MHz): δ 7.09-7.12 (m, 1H), 6.96-6.99 (m, 1H), 6.87-6.92 (m, 1H), 6.45 (s, lH), 6.27 (s 2H), 3.59 (s, 2H), 2.59-2.62 (m, 2H), 2.26 (s, 2H), 2.13 (s, 6H), 1.79-1.83 (m, 2H), 1.69 (s, 2H), 1.13 (s, 9H).
实施例二百二十二  Embodiment two hundred twenty two
N- (4- (7-氯 -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓小基） -2,6-二甲基） 3，3-二甲基丁酰胺的制  N-(4-(7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepine)-,2,6-dimethyl) 3,3-dimethyl Preparation of butanamide
Figure imgf000162_0001
Figure imgf000162_0001
6-氯 -3,4-二氢萘 -1 (2H) -酮 （化合物 222A)  6-Chloro-3,4-dihydronaphthalene-1(2H)-one (Compound 222A)
将化合物 6-氨基 -3,4-二氢萘 -1 (2H) -酮 （1.80 g， 0.011 mol) 悬浮于 3 mL盐酸和 3 mL 水的混合溶液中， 加入亚硝酸钠（83 mg， 0.012 mmol)。 降温至 0°C， 分批加入氯化亚铜（2.18 g, 0.022 mol) 。 加完后， 室温搅拌 2小时。 加水， 乙酸乙酯萃取， 合并， 干燥， 经石油醚过 柱纯化得产品 ( 1.39 g, 70% 收率） 。 MS: 181.1 (M+H+). The compound 6-amino-3,4-dihydronaphthalene-1 (2H)-one (1.80 g, 0.011 mol) was suspended in a mixed solution of 3 mL of hydrochloric acid and 3 mL of water, and sodium nitrite (83 mg, 0.012) was added. Mm). The temperature was lowered to 0 ° C, and cuprous chloride (2.18 g, 0.022 mol) was added in portions. After the addition was completed, the mixture was stirred at room temperature for 2 hours. Add water, extract with ethyl acetate, combine, dry, and purify with petroleum ether to afford product ( 1.39 g, 70% yield). MS: 181.1 (M+H + ).
6—氯 -3,4-二氢萘 -1 (2H) -酮肟 （化合物 222B)  6-Chloro-3,4-dihydronaphthalene-1 (2H)-ketooxime (Compound 222B)
将化合物 222A ( 1.39 g， 7.70 mmol)溶于 20 mL甲醇溶液中，加入盐酸羟胺（642 mg， 9.24 mmol) 和醋酸钠 （758 mg， 9.24 mmol)。 回流搅拌反应 1小时。 滤除反应液中的固体， 经石 油醚 /乙酸乙酯 =30:1过柱纯化得产品 （1.30 g，86%收率）。 MS: 196.1 (M+H+). Compound 222A ( 1.39 g, 7.70 mmol) was dissolved in 20 mL MeOH. EtOAc (EtOAc, EtOAc (EtOAc) The reaction was stirred at reflux for 1 hour. The solid in the reaction mixture was filtered, and purified with petroleum ether/ethyl acetate=30:1 to afford product (1.30 g, 86% yield). MS: 196.1 (M+H + ).
7-氯 -4,5-二氢 -1H-苯并 [b]氮杂卓 -2 (3H) -酮 （化合物 222C)  7-Chloro-4,5-dihydro-1H-benzo[b]azepine-2 (3H)-one (Compound 222C)
将化合物 222B ( 1.30 g, 6.64 mmol) 溶解于 15 mL多聚磷酸中， 90°C搅拌过夜。 小心加 水稀释， 乙酸乙酯萃取， 合并， 干燥并浓縮得产品 （1.25 g，96%收率） 。 MS: 196.1 (M+H+). Compound 222B (1.30 g, 6.64 mmol) was dissolved in 15 mL of polyphosphoric acid and stirred at 90 ° C overnight. Dilute with water carefully, extract with ethyl acetate, combine, dry and concentrate to give product (1.25 g, 96% yield). MS: 196.1 (M+H + ).
7-氯 -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓 （化合物 222D)  7-Chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (Compound 222D)
将化合物 222C ( 1.25 g， 6.39 mmol)溶于 20 mL四氢呋喃溶液中， 0°C下加入 1M的硼烷 -四氢呋喃溶液 （25.5 mL， 25.56 mmol )。 回流搅拌过夜。 用饱和的氢氧化钠水溶液将反应液 调成碱性，乙酸乙酯萃取，合并，干燥，经石油醚 /乙酸乙酯 =10:1过柱纯化得产品（1.15 g， 99% 收率）。 MS: 182.1 (M+H+). Compound 222C (1.25 g, 6.39 mmol) was dissolved in 20 mL EtOAc (EtOAc m. Stir at reflux overnight. The reaction mixture was made basic with aq. EtOAc. EtOAc (EtOAc) MS: 182.1 (M+H + ).
N- (4- (7-氯 -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓小基） -2,6-二甲基） 3，3-二甲基丁酰胺 （化 合物 222) 本品由化合物 222D ( 128 mg， 0.70 mmo ) 和 N- (4-溴 -2,6-二甲基苯基） -3,3-二甲基叔丁 基甲基酰胺 （230 mg， 0.77 mmol) 按照化合物 120的制备方法合成， 旋除溶剂， 粗品经制备 分离， 用盐酸***溶液酸化得其盐酸盐， 为黄色固体 222 ( 160 mg， 52%收率） 。 MS: 399.3 (M+H+). 1H NMR (400 MHz, DMSO- 6) δ: 8.81 (s， 1H)， 7.43-7.44 (d， J= 2.4 Hz, 1H)， 7.27-7.30 (m， 1H)， 7.09-7.11 (d, J= 8.4 Hz, 1H), 6.28 (s， 2H), 3.59 (s， 2H), 2.58-2.61 (m， 2H), 2.16 (s， 2H), 2.01 (s， 6H)， 1.74 (brs, 2H), 1.61 (brs, 2H), 1.04 (s， 9H). N-(4-(7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepine)-,2,6-dimethyl) 3,3-dimethyl Butanamide (compound 222) This product consists of compound 222D (128 mg, 0.70 mmo) and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-tert-butylmethylamide (230 mg, 0.77 mmol). The preparation of the compound 120 was carried out, the solvent was evaporated, and the crude product was purified by ethylamine (ethyl acetate) to give the hydrochloride salt as a yellow solid 222 (160 mg, 52% yield). MS: 399.3 (M+H+). 1H NMR (400 MHz, DMSO-6) δ: 8.81 (s, 1H), 7.43-7.44 (d, J = 2.4 Hz, 1H), 7.27-7.30 (m, 1H) , 7.09-7.11 (d, J= 8.4 Hz, 1H), 6.28 (s, 2H), 3.59 (s, 2H), 2.58-2.61 (m, 2H), 2.16 (s, 2H), 2.01 (s, 6H) ), 1.74 (brs, 2H), 1.61 (brs, 2H), 1.04 (s, 9H).
实施例二百二十三  Example two hundred twenty three
氮 -(4-(7-溴 -2，3，4，5-四氢 -1 氢 -苯并 [b]环己胺 -1-基) -2,6-二甲苯基) -3,3-二甲基丁酰胺的制 备
Figure imgf000163_0001
Nitrogen-(4-(7-bromo-2,3,4,5-tetrahydro-1 hydrogen-benzo[b]cyclohexylamine-1-yl)-2,6-dimethylphenyl)-3,3 -Preparation of dimethylbutyramide
Figure imgf000163_0001
6-溴 -3,4-二氢萘 -1(2氢) -羟胺 （化合物 223A)  6-Bromo-3,4-dihydronaphthalene-1(2H)-hydroxylamine (Compound 223A)
6-溴 3,4-二氢萘 -1(2氢) -酮 （2.0 g， 8.93 mmol), 盐酸羟氨 （745 mg， 10.72 mmol), 乙酸钠 (879 mg, 10.72 mmol) 在甲醇 （20M1) 中回流搅拌两小时。 旋干溶剂， 剩余物中加入乙酸乙酯 (100 mL), 分别用水和饱和食盐水洗涤一次， 无水硫酸钠干燥后减压浓縮得到产物 (2.0 g， 95%) ， 黄色固体。  6-Bromo 3,4-dihydronaphthalene-1(2H)-one (2.0 g, 8.93 mmol), Hydroxylamine hydrochloride (745 mg, 10.72 mmol), Sodium acetate (879 mg, 10.72 mmol) in methanol (20M1) The mixture was stirred under reflux for two hours. The solvent was evaporated, and EtOAc EtOAc m.
7-溴 -4,5-二氢 -1氢 -苯并 [b]己内酰胺 -2(3氢) -酮 （化合物 223B)  7-Bromo-4,5-dihydro-1hydrogen-benzo[b]caprolactam-2(3H)-one (Compound 223B)
化合物 223A C2.0 g， 8.37 mmol) 在多聚磷酸 （lO mL) 中于 90 °C搅拌过夜。 反应完毕后 倒入水中， 分别用 20毫升乙酸乙酯萃取三次， 合并有机相， 用饱和食盐水洗涤一次， 无水硫 酸钠干燥后减压浓縮得产物 (1.8 g， 90%) ， 黄色固体。  Compound 223A C2.0 g, 8.37 mmol) was stirred at <RTI ID=0.0></RTI> <RTIgt; After the completion of the reaction, the mixture was poured into water and extracted with EtOAc EtOAc EtOAc EtOAc. .
7-溴 -2，3，4，5-四氢 -1氢 -苯并 [b]环己胺 （化合物 223C)  7-Bromo-2,3,4,5-tetrahydro-1hydrogen-benzo[b]cyclohexylamine (Compound 223C)
化合物 223B (1.2 g， 5 mmol), 硼烷 （1M， 25 mL, 25 mmol) 在四氢呋喃 （10 mL)中回流搅 拌过夜， 然后加入 10毫升 2M 的盐酸， 继续回流搅拌两小时， 旋干溶剂， 剩余物溶于 100 毫升乙酸乙酯中， 饱和食盐水洗涤一次， 无水硫酸钠干燥， 减压浓縮后， 硅胶柱层析 （石油 醚 /乙酸乙酯 =10/1 ) 得到产物 (1.0 g, 88%) ， 黄色固体。  Compound 223B (1.2 g, 5 mmol), borane (1M, 25 mL, 25 mmol) EtOAc EtOAc (EtOAc) The residue was dissolved in ethyl acetate (100 ml), EtOAc (EtOAc) , 88%), yellow solid.
氮—(4-(7-溴 -2，3，4，5-四氢 -1 氢 -苯并 [b]环己胺 -1-基) -2,6-二甲苯基) -3,3-二甲基丁酰胺 （化 合物 223 )  Nitrogen-(4-(7-bromo-2,3,4,5-tetrahydro-1 hydrogen-benzo[b]cyclohexylamine-1-yl)-2,6-dimethylphenyl)-3,3 -dimethylbutyramide (compound 223)
本品由化合物 223C (736 mg, 3.27 mmol)和氮 -(4-溴 -2,6-二甲苯基) -3,3-二甲基丁酰胺 (1.01 g， 3.60 mmol) 按照化合物 120的制备方法合成， 110°C反应 2小时， 纯化得化合物 223 (100 mg， 7%), 黄色固体。 LCMS: [M+l]+:443; 1H NMR (CDC13- , 400MHz): δ 7.7.43 (d， J= 2.4 Hz, 2H), 7.34 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.04 (d, J= 8.0 Hz, 1H), 6.46 (s, 1H), 6.34 (s, 2H), 3.61 (m， 2H), 2.64 (t, J = 5.6 Hz, 2H), 2.28 (s， 2H), 2.14 (s， 1H), 1.82 (m， 2H), 1.69 (m， 2H), 1.04 (s， 9H). Preparation of compound 223C (736 mg, 3.27 mmol) and nitrogen-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (1.01 g, 3.60 mmol) according to compound 120 The method was synthesized and reacted at 110 ° C for 2 hours to obtain compound 223. (100 mg, 7%), yellow solid. LCMS: [M+l] + : 443; 1H NMR (CDC1 3 - , 400 MHz): δ 7.7.43 (d, J = 2.4 Hz, 2H), 7.34 (dd, J = 8.0 Hz, 2.0 Hz, 1H) , 7.04 (d, J= 8.0 Hz, 1H), 6.46 (s, 1H), 6.34 (s, 2H), 3.61 (m, 2H), 2.64 (t, J = 5.6 Hz, 2H), 2.28 (s, 2H), 2.14 (s, 1H), 1.82 (m, 2H), 1.69 (m, 2H), 1.04 (s, 9H).
实施例二百二十四  Embodiment two hundred twenty four
N-(2 -二甲基 -4-(2，3，4，5-四氢 -1H-苯并 [b]氮杂 -1-基)苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000164_0001
N-(2-dimethyl-4-(2,3,4,5-tetrahydro-1H-benzo[b]aza-1-yl)phenyl)-3,3-dimethylbutanamide Preparation
Figure imgf000164_0001
6-甲基 -3,4-二氢萘酚 -1(2H)-酮 （化合物 224A)  6-Methyl-3,4-dihydronaphthol -1(2H)-one (Compound 224A)
1-四氢萘酮 （4.0 g， 26.8 mmol), 乙酸钠 （2.64 g， 32.2 mmol) 和盐酸羟胺 （2.42 g， 32.2 mmol) 溶于甲醇 （12 mL) 中， 升温至回流反应 1 小时， 反应结束加入乙酸乙酯 （50 mL)稀 释， 然后加入 2 N氢氧化钠溶液 （13 mL) ， 减压旋干有机溶剂， 加入水 （40 mL) 和乙酸乙 酯 （80 mL)， 水层在用乙酸乙酯萃取 （50 mL)， 用食盐水 （50 mL) 洗有机层， 减压旋干溶剂 得到棕色的粗产品 （4.4 g， 产率 100%)。  1-tetralone (4.0 g, 26.8 mmol), sodium acetate (2.64 g, 32.2 mmol) and hydroxylamine hydrochloride (2.42 g, 32.2 mmol) dissolved in methanol (12 mL), warmed to reflux for 1 h, reaction At the end of the addition of ethyl acetate (50 mL) diluted, then 2 N sodium hydroxide solution (13 mL) was added, and the organic solvent was evaporated under reduced pressure. Water (40 mL) and ethyl acetate (80 mL) The organic layer was extracted with EtOAc (EtOAc) (EtOAc)
6—甲基—3,4-二氢 -1H-苯并 [b]氮杂环庚烯 -2 ( 3H) -酮 （化合物 224B )  6-methyl-3,4-dihydro-1H-benzo[b]azepine-2(3H)-one (compound 224B)
化合物 224A (4.4 g， 27.3 mmol) 加入到多聚磷酸 （120 g) 中， 升温至 80 °C 反应 16 小 时， 将反应液加入到水 （50 mL) 中溶解，乙酸乙酯萃取 （50 mLx3 ) ， 合并有机层干燥， 减压 旋干， 乙醇重结晶得产物 （3.8 g， 产率 84% ).  Compound 224A (4.4 g, 27.3 mmol) was added to polyphosphoric acid (120 g), and the mixture was warmed to 80 ° C for 16 hours. The reaction solution was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL×3) The combined organic layer was dried, dried under reduced pressure, and then recrystallized from ethanol to give product (3.8 g, yield 84%).
6-甲基- 2，3，4，5-四氢 -1H-苯并 [b]氮杂 （化合物 224C)  6-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (Compound 224C)
在 0 °C 下， 将溶有四氢锂铝 （2.0 g， 54 mmol) 的四氢呋喃 （75 mL) 溶液慢慢滴加 到溶有化合物 224B (2.5 g， 15.5 mmol) 的四氢呋喃 （20 mL) 溶液中， 滴加完毕后， 升温至 回流反应 24 小时， 冷却到室温， 用 20%的氢氧化钾溶液淬灭， 固体过滤， 有机相用无 水硫酸钠干燥， 减压旋干得到无色液体 （1.84 g， 产率 81%)。  A solution of lithium tetrahydrogen aluminum (2.0 g, 54 mmol) in tetrahydrofuran (75 mL) was slowly added dropwise to a solution of compound 224B (2.5 g, 15.5 mmol) in tetrahydrofuran (20 mL) at 0 °C. After the completion of the dropwise addition, the mixture was heated to reflux for 24 hours, cooled to room temperature, quenched with 20% potassium hydroxide solution, and filtered, and then dried over anhydrous sodium sulfate. 1.84 g, yield 81%).
N-(2，6-二甲基 -4-(2，3，4，5-四氢 -1H-苯并 [b]氮杂 -1- 基)苯基) -3,3-二甲基丁酰胺 （化合物 N-(2,6-Dimethyl-4-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)phenyl)-3,3-dimethyl Butanamide
224) 224)
本品由化合物 224C (323.4 mg， 2.2 mmol)和 N- (4-溴代 -2,6-二甲基苯基） -3-甲基丁酰胺 (600 mg， 2 mmol)按照化合物 120的制备方法合成， 100°C 反应 4 小时，纯化得目标产物 (200 mg， 产率 27%)， MS: 365 (； M+H+)。 iHNMR (DMSO, 400 MHz): δ 7.08(m, 3H), 6.46 (s， 1H), 6.32 (s， 2H), 3.36 (s, 2H), 2.62 (m， 2H), 2.38 (s, 3H), 2.27 (s, 2H), 2.14 (s, 6H)， 1.84 (s, 3H), 1.82 (s, 2H) 1.14 (s, 9H). Preparation of compound 224C (323.4 mg, 2.2 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3-methylbutanamide (600 mg, 2 mmol) according to compound 120 The method was synthesized and reacted at 100 ° C for 4 hours to obtain the target product (200 mg, yield 27%), MS: 365 (M+H+). iHNMR (DMSO, 400 MHz): δ 7.08 (m, 3H), 6.46 (s, 1H), 6.32 (s, 2H), 3.36 (s, 2H), 2.62 (m, 2H), 2.38 (s, 3H) , 2.27 (s, 2H), 2.14 (s, 6H), 1.84 (s, 3H), 1.82 (s, 2H) 1.14 (s, 9H).
实施例二百二十五  Example two hundred twenty five
N- (4- (2-氟 -4,5-二氢噻吩 [2，3-c]吡 -6 (7H)) -2,6-二甲基苯基） 3，3-二甲基丁酰胺的制备
Figure imgf000165_0001
N-(4-(2-Fluoro-4,5-dihydrothiophene[2,3-c]py-6(7H))-2,6-dimethylphenyl) 3,3-dimethylbutyl Preparation of amide
Figure imgf000165_0001
叔丁基 4，5-二氢噻吩 [2，3-c]吡啶 （化合物 225A)  tert-Butyl 4,5-dihydrothiophene [2,3-c]pyridine (Compound 225A)
4，5，6，7-四氢噻吩 [2，3-c]吡啶的盐酸盐 (1 g， 5.7 mmol)和三乙胺 (3.1 mL, 22.8 mmol)溶于 50 mL二氯甲烷后，于 0 °〇加入二叔丁基二甲酸酐 C1.8 g， 8.6 mmol),反应液室温搅拌 30 min后， 减压旋干溶剂， 剩余物水洗， 乙酸乙酯萃取， 石油醚： 乙酸乙酯 =10:1分离纯化得目标物为液 体 (1.2 g， 88% 收率) . MS: 240 (M+H+).  After the hydrochloride salt of 4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (1 g, 5.7 mmol) and triethylamine (3.1 mL, 22.8 mmol) were dissolved in 50 mL dichloromethane. Add di-tert-butyldicarboxylic anhydride C1.8 g, 8.6 mmol) at 0 °, and stir the reaction mixture at room temperature for 30 min. The solvent was evaporated and evaporated. =10:1 The target was isolated and purified as liquid (1.2 g, 88% yield). MS: 240 (M+H+).
2-氟 -4,5-二氢噻吩 [2，3-c]吡啶 -6 (7H) -甲酸叔丁酯 （化合物 225B)  2-Fluoro-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 225B)
化合物 225A(0.5 g， 2 mmol)溶于 20 mL无水四氢呋喃后降温至 -78 ，滴加正丁基锂（1.6 M， 1.7 mL, 2.8 mmol)后继续搅拌 1 h。 -78 °C滴加 N-氟 -N- (苯磺酰基）苯磺酰胺 (819 mg, 2.6 mmol)的 10 mL的四氢呋喃溶液， 滴加完成后， 反应液升至室温继续搅拌 8 h， 滴加水， 乙酸 乙酯萃取， 石油醚： 乙酸乙酯 =10:1分离纯化得目标物为液体（170 mg， 33%收率）。 MS: 258 (M+H+).  Compound 225A (0.5 g, 2 mmol) was dissolved in 20 mL of dry THF and then cooled to -78, and n-butyllithium (1.6 M, 1.7 mL, 2.8 mmol) was added dropwise and stirring was continued for 1 h. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (819 mg, 2.6 mmol) in 10 mL of tetrahydrofuran was added dropwise at -78 °C. After the dropwise addition was completed, the reaction mixture was stirred at room temperature and stirred for 8 h. Add water, extract with ethyl acetate, petroleum ether: ethyl acetate = 10:1. The title compound was obtained as a liquid (170 mg, 33% yield). MS: 258 (M+H+).
2-氟 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 225C)  2-fluoro-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (compound 225C)
化合物 225B (170 mg， 0.66 mmol)溶于 3 mL二氯甲烷后，于 0 °C加入三氟乙酸（3 mL)， 反应液室温搅拌 30 min后，减压旋干溶剂，所得物直接用于下一步反应（100 mg， 97%收率）。 MS: 158 (M+H+).  After compound 225B (170 mg, 0.66 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 30 min. The next reaction (100 mg, 97% yield). MS: 158 (M+H+).
N- (4- (2-氟 -4,5-二氢噻吩 [2，3-c]吡 -6 (7H)) -2,6-二甲基苯基） 3，3-二甲基丁酰胺 （化合 物 225 )  N-(4-(2-Fluoro-4,5-dihydrothiophene[2,3-c]py-6(7H))-2,6-dimethylphenyl) 3,3-dimethylbutyl Amide (compound 225)
本品由化合物 225C(100 mg， 0.64 mmol)和 N- (4-溴 -2,6-二甲基苯基） -3,3-二甲基丁酰胺 (200 mg, 0.67 mmol) 按照化合物 115的制备方法合成， 封管中 120°C反应 8 h， 纯化得目标化 合物， 为黄色固体 (20 mg, 8% 收率） 。 1H NMR ( -DMSO, 400 MHz) δ: 8.89 (brs, 1H), 6.71 (s, 2H), 6.45 (s, 1H), 4.26 (s, 2H), 3.55 (t, J = 11, 2H), 2.60 (t, J = 11, 2H), 2.16 (s, 2H), 2.08 (s, 6H)， 1.04 (s， 9H). MS: 375 (M+H+). This product consists of compound 225C (100 mg, 0.64 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) according to compound 115 The preparation method was synthesized, and the reaction was carried out at 120 ° C for 8 h in a sealed tube to obtain the target compound as a yellow solid (20 mg, 8% yield). 1H NMR (-DMSO, 400 MHz) δ: 8.89 (brs, 1H), 6.71 (s, 2H), 6.45 (s, 1H), 4.26 (s, 2H), 3.55 (t, J = 11, 2H), 2.60 (t, J = 11, 2H), 2.16 (s, 2H), 2.08 (s, 6H), 1.04 (s, 9H). MS: 375 (M+H + ).
实施例二百二十六  Example two hundred twenty six
N-(4-(2-氯 -4，5-二氢噻吩 [2，3-c]吡啶 -6(7H)-2，6-二甲基苯基) -3，3-二甲基丁酰胺的制备
Figure imgf000166_0001
N-(4-(2-chloro-4,5-dihydrothiophene[2,3-c]pyridine-6(7H)-2,6-dimethylphenyl)-3,3-dimethylbutyl Preparation of amide
Figure imgf000166_0001
2-氯 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 226A)  2-Chloro-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (Compound 226A)
4，5，6，7-四氢噻吩 [2，3-c]吡啶的盐酸盐 （595 mg， 3.4 mmol) 溶于 10 mL乙腈后， 将溴 N-氯 代丁二酰亚胺 （545 mg， 4.08 mmol) 的醋酸溶液慢慢加入， 反应液室温搅拌 3 h后， 反应液 用水洗， 乙酸乙酯萃取， 无水硫酸钠干燥， 真空旋干溶剂， 柱层析得产物 550 mg， 收率 93%。  4,5,6,7-Tetrahydrothiophene [2,3-c]pyridine hydrochloride (595 mg, 3.4 mmol) After dissolving in 10 mL of acetonitrile, bromo N-chlorosuccinimide (545) The acetic acid solution of mg, 4.08 mmol) was slowly added. After the reaction mixture was stirred at room temperature for 3 h, the reaction mixture was washed with water, ethyl acetate and dried over anhydrous sodium sulfate. The rate is 93%.
N-(4-(2-氯 -4,5-二氢噻吩 [2，3-c]吡啶 -6(7H)-2，6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 N-(4-(2-chloro-4,5-dihydrothiophene[2,3-c]pyridine-6(7H)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide
226) 226)
本品由 2-氯 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （550 mg， 3.18 mmol)和 N-(4-溴 -2,6-二甲基苯 基) -3,3-二甲基丁酰胺 （1.13 g， 3.81 mmol) 按照化合物 115的制备方法合成， 封管中 120°C反应 8 h，纯化得产物 200 mg，收率 25%。 MS: 391 (M+H+)。 iHNMR (DMSO, 400 MHz): δ 8.88 (s, 1H), 6.85 (s, 1H), 6.71 (s, 2H), 4.32 (s,2H), 3.53-3.55 (m， 2H), 2.62-2.65 (m， 2H), 2.16 (s, 2H), 2.08 (s, 6H)， 1.04 (s, 9H)。  This product consists of 2-chloro-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (550 mg, 3.18 mmol) and N-(4-bromo-2,6-dimethylphenyl) -3,3-Dimethylbutanamide (1.13 g, 3.81 mmol) was synthesized according to the preparation method of compound 115, and was subjected to a reaction at 120 ° C for 8 h in a sealed tube to obtain a product of 200 mg in a yield of 25%. MS: 391 (M+H+). iHNMR (DMSO, 400 MHz): δ 8.88 (s, 1H), 6.85 (s, 1H), 6.71 (s, 2H), 4.32 (s, 2H), 3.53-3.55 (m, 2H), 2.62-2.65 ( m, 2H), 2.16 (s, 2H), 2.08 (s, 6H), 1.04 (s, 9H).
实施例二百二十七  Example two hundred twenty seven
N-(4-(2-溴 -4 5-二氢噻吩 [2，3-c]吡啶 -6(7H)-2，6-二甲基苯基) -3，3-二甲基丁酰胺的制备 N- (4-(2-bromo-4 5-dihydrothiophene[2,3-c]pyridine-6(7H)-2,6-dimethylphenyl)-3,3-dimethylbutanamide Preparation
Figure imgf000166_0002
Figure imgf000166_0002
2-溴 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 227A)  2-Bromo-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (Compound 227A)
4，5，6，7-四氢噻吩 [2，3-c]吡啶的盐酸盐 （600 mg， 3.4 mmol) 溶于 20 mL醋酸后，将溴 （0.18 mL,3.48 mmol) 的醋酸溶液慢慢加入， 反应液室温搅拌 1.5 h后， 固体过滤， 固体用***洗， 油泵抽干得到固体产物 （353 mg，30% 收率)。  4,5,6,7-tetrahydrothiophene [2,3-c]pyridine hydrochloride (600 mg, 3.4 mmol) After dissolving in 20 mL of acetic acid, bromine (0.18 mL, 3.48 mmol) in acetic acid was slow. After slowly adding, the reaction mixture was stirred at room temperature for 1.5 h, then filtered and evaporated and evaporated.
2-溴 -6-(3，5-二甲基 -4-硝基) -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 227B)  2-Bromo-6-(3,5-dimethyl-4-nitro)-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (Compound 227B)
2-溴 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （353 mg， 1.62 mmol), 5-氟 -1,3-二甲基 -2-硝基苯 (300 mg， 2.52 mmol),碳酸钾 （1.12 g， 8.1 mmol) 溶于 10 mL N，N-二甲基甲酰胺中， 反应液在 150 °〇搅 拌 48 h后， 反应液用水洗， 乙酸乙酯萃取， 无水硫酸钠干燥， 真空旋干溶剂， 柱层析得产物 70 mg, 收率 12%。 4-(2-溴 -4，5-二氢噻吩 [2，3-c]吡啶 -6(7H))-2，6-二甲基苯胺 （化合物 227C) 2-Bromo-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (353 mg, 1.62 mmol), 5-fluoro-1,3-dimethyl-2-nitrobenzene (300 Mg, 2.52 mmol), potassium carbonate (1.12 g, 8.1 mmol) dissolved in 10 mL of N,N-dimethylformamide. After stirring at 150 ° C for 48 h, the reaction mixture was washed with water and ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. 4-(2-Bromo-4,5-dihydrothiophene[2,3-c]pyridine-6(7H))-2,6-dimethylaniline (Compound 227C)
2-溴 -6- (3,5-二甲基 -4-硝基） -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （70 mg， 0.19 mmol), 连二亚硫 酸钠 （330 mg， 1.9 mmol) 溶于 5 mL 甲醇和 1 mL水中， 在 90 °C下反应 lh， 过滤， 真空 旋干得产物 （50 mg， 83% yield)。  2-Bromo-6-(3,5-dimethyl-4-nitro)-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (70 mg, 0.19 mmol), Sodium sulfite (330 mg, 1.9 mmol) was dissolved in 5 mL of methanol and 1 mL of water, and then reacted at 90 ° C for 1 h, filtered, and evaporated to dryness (50 mg, 83% yield).
N-(4-(2-溴 -4,5-二氢噻吩 [2，3-c]吡啶 -6(7H)-2，6-二甲基苯基) -3,3-二甲基丁酰胺 （化合物 N- (4-(2-Bromo-4,5-dihydrothiophene[2,3-c]pyridine-6(7H)-2,6-dimethylphenyl)-3,3-dimethylbutyl Amide
227) 227)
4-(2-溴 -4,5-二氢噻吩 [2，3-c]吡啶 -6(7H)-2，6-二甲基苯胺 （50 mg， 0.15 mmol),碳酸钾 （62.1 mg, 0.45 mmol) 溶于 5 mL 四氢呋喃中，然后将 3,3-二甲基丁酰氯 （25 L， 0.18 mmol) 慢 慢滴加到反应液中， 在室温下反应 16h 小时， 反应液用水洗， 乙酸乙酯萃取， 无水硫酸 钠干燥，真空旋干溶剂，柱层析得产物 25 mg,收率 38%。 MS: 435 CM+H+)。 i iNMR (CDC13， 400 MHz): δ 6.74 (s, 1H)， 6.67 (s, 2H), 6.50 (s, 1H)， 4.28 (s,2H), 3.51-3.54 (m， 2H), 2.72 (s, 2H), 2.26 (s， 2H), 2.15 (s， 2H), 1.99 (s， 6H)， 1.13 (s, 9H)。 4-(2-Bromo-4,5-dihydrothiophene[2,3-c]pyridine-6(7H)-2,6-dimethylaniline (50 mg, 0.15 mmol), potassium carbonate (62.1 mg, 0.45 mmol) was dissolved in 5 mL of tetrahydrofuran, then 3,3-dimethylbutyryl chloride (25 L, 0.18 mmol) was slowly added dropwise to the reaction solution, and reacted at room temperature for 16 h, the reaction solution was washed with water, acetic acid. extracted with ethyl, dried over anhydrous sodium sulfate, and rotary evaporation in vacuo, the product by column chromatography to give 25 mg, yield 38% MS:. 435 CM + H +). i iNMR (CDC1 3 , 400 MHz): δ 6.74 (s, 1H), 6.67 (s, 2H), 6.50 (s, 1H), 4.28 (s, 2H), 3.51-3.54 (m, 2H), 2.72 ( s, 2H), 2.26 (s, 2H), 2.15 (s, 2H), 1.99 (s, 6H), 1.13 (s, 9H).
实施例二百二十八  Example two hundred twenty eight
N-(-(2-甲基 -4，5-二氢噻吩 [2，3-c]吡 -6(7H》-2，6-二甲基苯基) 3，3-二甲基丁酰胺的制备
Figure imgf000167_0001
N-(-(2-methyl-4,5-dihydrothiophene[2,3-c]py-6(7H)-2,6-dimethylphenyl) 3,3-dimethylbutanamide Preparation
Figure imgf000167_0001
叔丁基 2-甲基 -4,5-二氢噻吩 [2，3-c]吡啶 （化合物 228A)  tert-Butyl 2-methyl-4,5-dihydrothiophene [2,3-c]pyridine (Compound 228A)
叔丁基 2-溴 -4,5-二氢噻吩 [2，3-c]吡啶 （694 mg, 2.17 mmol), 三甲基环三硼氧烷 (1.09 g， 8.68 mmol), 四三苯基膦钯 （231 mg， 0.2 mmol), 碳酸钾 （900 mg， 6.5mmol) 加入到 10 mL 1，4-二氧六环中， 在氮气保护下， 120 °C反应 4 h， 减压旋干溶剂， 剩余物水洗， 乙酸乙酯萃 取， 柱层析得产物 （353 mg，64% 收率)。  tert-Butyl 2-bromo-4,5-dihydrothiophene [2,3-c]pyridine (694 mg, 2.17 mmol), trimethylcyclotriboroxane (1.09 g, 8.68 mmol), tetratriphenyl Palladium phosphine (231 mg, 0.2 mmol), potassium carbonate (900 mg, 6.5 mmol) was added to 10 mL of 1,4-dioxane, reacted at 120 ° C for 4 h under nitrogen, and the solvent was evaporated under reduced pressure. The residue was washed with water, ethyl acetate (EtOAc)
2-甲基 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 228B)  2-methyl-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (compound 228B)
叔丁基 2-甲基 -4,5-二氢噻吩 [2，3-c]吡啶 （353 mg, 1.39 mmol) 溶于 20 mL二氯甲烷后， 于 0 °C加入三氟乙酸（0.5 mL)， 反应液室温搅拌 3 h后， 减压旋干溶剂， 所得物直接用于下一步 反应 (100 mg, 47%收率）。  tert-Butyl 2-methyl-4,5-dihydrothiophene [2,3-c]pyridine (353 mg, 1.39 mmol) dissolved in 20 mL of dichloromethane, then added trifluoroacetic acid (0.5 mL) at 0 °C After the reaction mixture was stirred at room temperature for 3 hr, the solvent was evaporated to dryness, and the obtained material was applied to the next step (100 mg, 47% yield).
N-(-(2-甲基 -4,5-二氢噻吩 [2，3-c]吡 -6(7H》-2，6-二甲基苯基) 3，3-二甲基丁酰胺（化合物 228) 本品由 2-甲基 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （100 mg, 0.65 mmol)和 N- (4-溴 -2,6-二甲基苯 基） -3,3-二甲基丁酰胺 （233 mg， 0.78 mmol) 按照化合物 115的制备方法合成， 封管中 120°C反 应 8 h， 纯化得目标化合物 (130 mg， 54% 收率)。 MS: 371 (M+H+)。 1HNMR (CDC13， 400 MHz): δ 6.68 (s, 2H), 6.50 (s, 1H), 6.44 (s, 1H), 4.32 (s,2H), 3.51-3.54 (m, 2H), 2.69-2.72 (m, 2H), 2.43 (s: 3H), 2.27 (s， 2H), 2.20 (s， 6H)， 1.14 (s， 9H). N-(-(2-methyl-4,5-dihydrothiophene[2,3-c]py-6(7H)-2,6-dimethylphenyl) 3,3-dimethylbutanamide (Compound 228) This product consists of 2-methyl-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (100 mg, 0.65 mmol) and N-(4-bromo-2,6- Dimethylphenyl)-3,3-dimethylbutyramide (233 mg, 0.78 mmol) was synthesized according to the preparation method of compound 115, and the reaction was carried out at 120 ° C for 8 h to obtain the target compound (130 mg, 54 % yield) MS: 371 (M+H + ) 1HNMR (CDC1 3 , 400 MHz): δ 6.68 (s, 2H), 6.50 (s, 1H), 6.44 (s, 1H), 4.32 (s, 2H), 3.51-3.54 (m, 2H), 2.69-2.72 (m, 2H), 2.43 (s : 3H), 2.27 (s, 2H), 2.20 (s, 6H), 1.14 (s, 9H).
实施例二百二十九  Example two hundred twenty nine
N-(-(2 备  N-(-(2)
Figure imgf000168_0001
Figure imgf000168_0001
2-溴 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 229A)  2-Bromo-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (Compound 229A)
4，5，6，7-四氢噻吩 [2，3-c]吡啶的盐酸盐 （3.5 g， 20 mmol) 溶于 20 mL醋酸后，将溴 （1.03 mL， 20.2 mmol) 的醋酸溶液慢慢加入， 反应液室温搅拌 1.5 h后， 固体过滤， 固体用***洗， 油泵 抽干得到固体产物 （4 g，70% 收率)。  4,5,6,7-tetrahydrothiophene [2,3-c]pyridine hydrochloride (3.5 g, 20 mmol) After dissolving in 20 mL of acetic acid, bromine (1.03 mL, 20.2 mmol) in acetic acid was slow. After slowly adding, the reaction mixture was stirred at room temperature for 1.5 h, then filtered and evaporated.
叔丁基 2-溴 -4,5-二氢噻吩 [2，3-c]吡啶 （化合物 229B)  tert-Butyl 2-bromo -4,5-dihydrothiophene [2,3-c]pyridine (Compound 229B)
2-溴 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （2.4 g， 8 mmol) 、 三乙胺 （4.5 mL， 32 mmol) 禾 B DMAP (98 mg， 0.8 mmol) 溶于 30 mL 四氢呋喃后， 于 0 °〇加入二叔丁基二甲酸酐 （3.49 g， 16 mmol), 反应液室温搅拌 16 h后， 减压旋干溶剂， 剩余物水洗， 乙酸乙酯萃取， 柱层析得产 物 （2.5 g，98% 收率)。  2-Bromo-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (2.4 g, 8 mmol), triethylamine (4.5 mL, 32 mmol), EtOAc (br.) After dissolving in 30 mL of tetrahydrofuran, di-tert-butyldicarboxylic anhydride (3.49 g, 16 mmol) was added at 0 °, and the reaction mixture was stirred at room temperature for 16 h, then the solvent was evaporated and evaporated. The product was obtained by column chromatography (2.5 g, 98% yield).
叔丁基 2-氰基 -4,5-二氢噻吩 [2，3-c]吡啶 （化合物 229C)  tert-Butyl 2-cyano-4,5-dihydrothiophene [2,3-c]pyridine (Compound 229C)
叔丁基 2-溴 -4,5-二氢噻吩 [2，3-c]吡啶 （634 mg，2 mmol)， 氰化锌 （235 mg， 2 mmol), 四三 苯基膦钯 （231 mg， 0.2 mmol) 加入到 30 mL N，N-二甲基甲酰胺， 在氮气保护下， 130 °〇反 应 3 h， 减压旋干溶剂， 剩余物水洗， 乙酸乙酯萃取， 柱层析得产物 （400 mg，77% 收率)。  tert-Butyl 2-bromo-4,5-dihydrothiophene [2,3-c]pyridine (634 mg, 2 mmol), zinc cyanide (235 mg, 2 mmol), tetratriphenylphosphine palladium (231 mg , 0.2 mmol) was added to 30 mL of N,N-dimethylformamide. Under nitrogen atmosphere, the reaction was carried out at 130 ° C for 3 h. The solvent was evaporated under reduced pressure. The residue was washed with water and ethyl acetate. (400 mg, 77% yield).
2-氰基 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （化合物 229D)  2-cyano-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (compound 229D)
叔丁基 2-氰基 -4,5-二氢噻吩 [2，3-c]吡啶 （400 mg， 1.52 mmol) 溶于 20 mL二氯甲烷后，于 0 °C加入三氟乙酸（0.5 mL)， 反应液室温搅拌 30 h后， 减压旋干溶剂， 所得物直接用于下一 步反应 （200 mg， 47%收率  tert-Butyl 2-cyano-4,5-dihydrothiophene [2,3-c]pyridine (400 mg, 1.52 mmol) After dissolving in 20 mL of dichloromethane, trifluoroacetic acid (0.5 mL) was added at 0 °C. After the reaction solution was stirred at room temperature for 30 h, the solvent was evaporated to dryness, and the obtained material was directly applied to the next reaction (200 mg, 47% yield)
N-(-(2-氰基 -4,5-二氢噻吩 [2，3-c]吡 -6(7H》-2，6-二甲基苯基) 3，3-二甲基丁酰胺（化合物 229) 本品由 2-氰基 -4，5，6，7-四氢噻吩 [2，3-c]吡啶 （200 mg， 1.22 mmol)禾口 N- (4-溴 -2,6-二甲基苯 基） -3,3-二甲基丁酰胺 （435 mg， 1.46 mmol) 按照化合物 115的制备方法合成， 封管中 120°C反 应 8 h, 纯化得目标化合物 (40 mg， 10% 收率）。 MS: 382 (M+H+)。 iHNMR (CDC13， 400 MHz): δ 7.33 (s, 1H), 6.67 (s, 2H), 6.52 (s, 1H), 4.41 (s,2H), 3.55-3.58 (m， 2H), 2.79-2.82 (m， 2H), 2.27 (s, 2H), 2.20 (s， 6H)， 1.14 (s, 9H)。 N-(-(2-Cyano-4,5-dihydrothiophene[2,3-c]py-6(7H)-2,6-dimethylphenyl) 3,3-dimethylbutanamide (Compound 229) This product consists of 2-cyano-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine (200 mg, 1.22 mmol) and N-(4-bromo-2,6 - dimethylphenyl) -3,3-dimethylbutyramide (435 mg, 1.46 mmol) was synthesized according to the preparation method of compound 115, and the reaction was carried out at 120 ° C for 8 h in a sealed tube to purify the target compound (40 mg, 10% yield) MS: 382 (M+H + ). iHNMR (CDC1 3 , 400 MHz): δ 7.33 (s, 1H), 6.67 (s, 2H), 6.52 (s, 1H), 4.41 (s , 2H), 3.55-3.58 (m, 2H), 2.79-2.82 (m, 2H), 2.27 (s, 2H), 2.20 (s, 6H), 1.14 (s, 9H).
实施例二百三十  Embodiment two hundred thirty
N-(2，6-二甲基 -4- ( 3-溴-4-2，5-二氢噻吩并[2，3-0 |吡啶-6 (7H) -二甲基苯基 )-3，3-二甲基苯 丁酰胺的制备  N-(2,6-Dimethyl-4-( 3-bromo-4-2,5-dihydrothieno[2,3-0 |pyridin-6(7H)-dimethylphenyl)-3 Preparation of 3-dimethylphenylbutanamide
Figure imgf000169_0001
Figure imgf000169_0001
2,3-二溴 -4，5，6，7-四氢噻吩并 [2，3-c]吡啶 （化合物 230A)  2,3-dibromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (Compound 230A)
4，5，6，7-四氢噻吩并 [2，3-c]吡啶 （1.75 g， 10 mmol) 溶于 20 mL无水二氯甲烷中， 冰浴搅 拌滴加入液溴（7.9 g， 50 mmol),室温下搅拌 12 h。滤液减压旋干，得目标物为黄色固体（3.3 g， 100%收率）。 MS: 298 (M+H+).  4,5,6,7-Tetrahydrothieno[2,3-c]pyridine (1.75 g, 10 mmol) was dissolved in 20 mL of dry methylene chloride. br. Methyl), stirred at room temperature for 12 h. The filtrate was dried under reduced pressure to give the title compound as a yellow solid (3.3 g, 100% yield). MS: 298 (M+H+).
叔丁基 -2,3-二溴 -2,5-二氢噻吩并 [2，3-c]吡啶 -6(7H)-甲酸叔丁酯 （化合物 230B) 化合物 230A (3.3g， 10 mmol)溶于 50 mL无水二氯甲烷中， 冰浴搅拌加入二碳酸二叔 丁基酯 （2.5 g， 12 mmol), 三乙胺 (5 g， 50 mmol)反应液室温搅拌 4 h， 滤液减压旋干， 得浅 黄色产物 （3.8 g， 97.9%) 。 MS: 396 (M+H+)。  tert-Butyl-2,3-dibromo-2,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 230B) Compound 230A (3.3 g, 10 mmol) Dissolve in 50 mL of anhydrous dichloromethane, add di-tert-butyl dicarbonate (2.5 g, 12 mmol), and stir the reaction mixture of triethylamine (5 g, 50 mmol) for 4 h at room temperature. Spin dry to give a pale yellow product (3.8 g, 97.9%). MS: 396 (M+H+).
3-溴 -4-叔丁基 -2,5-二氢噻吩并 [2，3-c]吡啶 -6 (7H) -甲级叔丁酯 （化合物 230C) 化合物 230B (3.9 g， 10 mmol), 溶解在无水 THF (20 mL) 中反应液在氮气保护下冷却 到零下 78摄氏度， 搅拌下滴加入正丁基锂（ 1.6 M， 8 mL, 12 mmol) 。保持零下 78摄氏度一 个小时， 反应液升至室温， 加入饱和 NH4C1淬灭， 乙酸乙酯萃取， 有机相无水硫酸钠干燥， 硅胶柱分离 （PE:EA= 5:1 ) 得黄色目标产物 230C (954 mg， 30%收率）， MS: 318 (M+H+), 叔 丁醇 3-溴 -2-丁基 -4-2,5-二氢噻吩并 [2，3-c]吡啶 -6 (7H) -甲酸叔丁酯（935 mg， 25%收率）， MS: 374(M+H+)。 3-Bromo-4-tert-butyl-2,5-dihydrothieno[2,3-c]pyridine-6(7H)-methyl-tert-butyl ester (Compound 230C) Compound 230B (3.9 g, 10 mmol) The reaction solution was dissolved in anhydrous THF (20 mL) and cooled to below &lt;RTI ID=0.0&gt;&gt; Holding minus 78 degrees Celsius for an hour, the reaction solution was raised to room temperature, quenched with saturated NH 4 C1, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, and separated by silica gel column (PE: EA = 5: 1 ) to give the desired product as a yellow 230C (954 mg, 30% yield), MS: 318 (M+H + ), tert-butanol 3-bromo-2-butyl-4-2,5-dihydrothieno[2,3-c] Pyridine-6(7H)-tert-butyl formate (935 mg, 25% yield), MS: 374 (M+H+).
3-溴 -4，5，6，7-二氢噻吩并 [2，3-c]吡啶 （化合物 230D)  3-bromo-4,5,6,7-dihydrothieno[2,3-c]pyridine (Compound 230D)
3-溴 -4-叔丁基 -2,5-二噻吩并 [2，3-c]吡啶（ 158 mg， 0.5 mmol)溶于 5 mL无水二氯甲烷中， 冰浴搅拌加入三氟乙酸（550 mg， 5 mmol) 反应液室温搅拌 4 h， 滤液减压旋干， 得浅黄色产 物 （100 mg，96%) 。 MS: 219 (M+H+).  3-Bromo-4-tert-butyl-2,5-dithieno[2,3-c]pyridine (158 mg, 0.5 mmol) was dissolved in 5 mL of anhydrous dichloromethane. (550 mg, 5 mmol) The reaction was stirred 4h EtOAc. MS: 219 (M+H+).
3-溴 -6-(3，5-二甲基 -4-硝基) -4，5，6，7-二氢噻吩并 [2，3-c]吡啶 （化合物 230E)  3-bromo-6-(3,5-dimethyl-4-nitro)-4,5,6,7-dihydrothieno[2,3-c]pyridine (Compound 230E)
本品由化合物 230D( 100 mg， 0.46 mmol)和 5-溴 -1,3-二甲基 -2-硝基苯 （106 mg， 0.46 mmol) 按照化合物 120的制备方法合成， 纯化得黄色目标产物 230E ( 100 mg， 27%收率）。 MS: 368 (M+H+). This product consists of compound 230D (100 mg, 0.46 mmol) and 5-bromo-1,3-dimethyl-2-nitrobenzene (106 mg, 0.46 mmol) The title compound 230E (100 mg, 27% yield) was obtained. MS: 368 (M+H+).
3-溴 -6-(3，5-二甲基 -4-胺基) -4，5，6，7-二氢噻吩并 [2，3-c]吡啶 （化合物 230F)  3-bromo-6-(3,5-dimethyl-4-amino)-4,5,6,7-dihydrothieno[2,3-c]pyridine (Compound 230F)
化合物 230E ( lOO mg, 0.27 mmol)溶于甲醇： 水 =9: 1溶液 5 mL， 搅拌加入保险粉 (470 mg， 2.7 mmol) 反应液加热到 90摄氏度搅拌 4 h， 反应完成。 反应液减压旋干， 得浅黄色产 物 （85mg， 95%) 。 MS: 338 (M+H+). Compound 230E (100 mg, 0.27 mmol) was dissolved in methanol: water = 9:1 solution 5 mL, stirred with stirring powder (470 mg, 2.7 mmol). The reaction mixture was heated to 90 ° C for 4 h and the reaction was completed. The reaction mixture was evaporated to dryness crystals crystals crystals MS: 338 (M+H + ).
N-(2，6-二甲基 -4- ( 3-溴-4-2，5-二氢噻吩并[2，3-0 |吡啶-6 (7H) -二甲基苯基 )-3，3-二甲基苯 丁酰胺 （化合物 230)  N-(2,6-Dimethyl-4-( 3-bromo-4-2,5-dihydrothieno[2,3-0 |pyridin-6(7H)-dimethylphenyl)-3 ,3-dimethylphenylbutanamide (compound 230)
化合物 230F ( 85 mg， 0.25 mmol)溶于 10 mL无水二氯甲烷中， 冰浴搅拌加入 3,3-二甲 基叔丁基酰氯 (50 mg， 0.35 mmol), 三乙胺 (101 mg，l mmol)反应液室温搅拌 4 h， 反应液减压 旋干，得浅黄色产物 126 ( 80 mg， 68%)。 i i NMR (DMSO, 400MHz): 58.93 (s, 1H)， 7.57 (s, 1H)， 6.79 (s, 2H), 4.47 (s, 2H), 3.61(m, 2H),2.59 (m， 2H), 2.18 (s, 2H), 2.10 (s, 6H).MS: 436 (M+H+). 实施例二百三 ^一 Compound 230F (85 mg, 0.25 mmol) was dissolved in 10 mL of dry methylene chloride. EtOAc (EtOAc, m. The reaction mixture was stirred at room temperature for 4 h. Ii NMR (DMSO, 400MHz): 58.93 (s, 1H), 7.57 (s, 1H), 6.79 (s, 2H), 4.47 (s, 2H), 3.61 (m, 2H), 2.59 (m, 2H), 2.18 (s, 2H), 2.10 (s, 6H). MS: 436 (M+H + ). Example two hundred three ^ one
N-(2，6-二甲基 -4- ( 3-甲基 -4-2,5-二氢噻吩并 [2，3-c]吡啶 -6 (7H) -二甲基苯基 )-3，3-二甲基 苯丁酰胺的制备  N-(2,6-Dimethyl-4-(3-methyl-4-2,5-dihydrothieno[2,3-c]pyridine-6(7H)-dimethylphenyl)- Preparation of 3,3-dimethylphenylbutanamide
Figure imgf000170_0001
Figure imgf000170_0001
叔丁基 -3 - 甲基 -4-2,5 - 二氢噻吩并 [2，3-c〕 吡啶 -6 (7H) -甲酸叔丁酯 （化合物 231A) 3-溴 -4-叔丁基 -2,5-二氢噻吩并 [2，3-c]吡啶 -6 (7H) -甲级叔丁酯 （620 mg， 2 mmol), 三甲 氧基环硼氧烷（6 g， 10 mmol), Pd(PPh3)4 (468 mg， 0.2 mmol), K2C03(828 mg， 6 mmol)溶于 1,4- 二氧六环中。 反应液在氮气保护下加热回流 12小时。 冷却至室温后， 滤液减压旋干， 硅胶柱 子分离 （PE:EA= 10:1 ) 得白色目标产物 （125 mg，51%) MS: 254(M+H+)。 tert-Butyl-3-methyl-4-2,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 231A) 3-bromo-4-tert-butyl -2,5-dihydrothieno[2,3-c]pyridine-6(7H)-methyl tert-butyl ester (620 mg, 2 mmol), trimethoxyboroxine (6 g, 10 mmol) , Pd(PPh 3 ) 4 (468 mg, 0.2 mmol), K 2 C0 3 (828 mg, 6 mmol) was dissolved in 1,4-dioxane. The reaction solution was heated to reflux for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the filtrate by rotary evaporation under reduced pressure, separated by silica gel column (PE: EA = 10: 1 ) to give the desired product as a white (125 mg, 51%) MS : 254 (M + H +).
3-甲基 -4，5，6，7-二氢噻吩并 [2，3-c]吡啶 （化合物 231B)  3-methyl-4,5,6,7-dihydrothieno[2,3-c]pyridine (compound 231B)
化合物 231 A ( 125 mg， 0.5 mmol)溶于 5 mL无水二氯甲烷中， 冰浴搅拌加入三氟乙酸 (550 mg, 5 mmol) 反应液室温搅拌 4 h， 滤液减压旋干， 得浅黄色产物 （ 100 mg， 97.9%) 。 MS: 154 (M+H+).  The compound 231 A (125 mg, 0.5 mmol) was dissolved in 5 mL of dry methylene chloride. Yellow product (100 mg, 97.9%). MS: 154 (M+H+).
N-(2，6-二甲基 -4- ( 3-甲基 -4-2,5-二氢噻吩并 [2，3-c]吡啶 -6 (7H) -二甲基苯基 )-3，3-二甲基 苯丁酰胺 （化合物 231 )  N-(2,6-Dimethyl-4-(3-methyl-4-2,5-dihydrothieno[2,3-c]pyridine-6(7H)-dimethylphenyl)- 3,3-dimethylphenylbutanamide (compound 231)
本品由化合物 231B(100 mg, 0.65 mmol)和 N-(4-溴 -2,6-二甲基苯基 -3,3-二甲基)苯丁酰胺 (194 mg, 0.65 mmol) 按照化合物 120的制备方法合成， 纯化得黄色目标产物 （50 mg，22%收 率）。 MS: 371 (M+H+). 1H NMR (DMSO, 400MHz): δ 6.77 (m， 2H), 6.54 (s， 1H), 4.41 (s， 2H), 3.59 (m， 2H), 3.59 (m， 2H), 2.28 (s， 2H), 2.21 (s， 6H)， 2.12 (s， 3H),1.14 (s， 9H). MS: 371 (M+H+). This product consists of compound 231B (100 mg, 0.65 mmol) and N-(4-bromo-2,6-dimethylphenyl-3,3-dimethyl)phenylbutanamide (194 mg, 0.65 mmol) was synthesized according to the procedure of compound 120 to yield the title compound (50 mg, 22% yield). MS: 371 (M+H + ). 1H NMR (DMSO, 400 MHz): δ 6.77 (m, 2H), 6.54 (s, 1H), 4.41 (s, 2H), 3.59 (m, 2H), 3.59 (m) , 2H), 2.28 (s, 2H), 2.21 (s, 6H), 2.12 (s, 3H), 1.14 (s, 9H). MS: 371 (M+H + ).
实施例二百三十二  Example two hundred thirty two
(a) 电生理实验方法：  (a) Electrophysiological test methods:
CHO细胞瞬时转染 KCNQ2通道， 在室温条件记录电流。 记录期间， 细胞用溶有化合物的 细胞外液 ( 140 mM NaCl, 5mM KC1, 2mM CaCl2, 1.5mM MgCl2， lOmM HEPES and lOmM Glucose, pH 7.4) 灌流。 电极 （阻抗 3-5兆欧） 用高硼硅玻璃吸管拉制 （ Sutter instrument BF150-86-10)，并充满细胞內液 ( 145 mM, KCl，lmM MgCl2， 5 EGTA, lOmM HEPES and 5mM Mg2+-ATP, pH 7.3 ) 。 数据用 Axopatch 200B 放大器（Molecular Device)采集， 信号经过频率 1kHz过滤并用软件 pClamplO交互界面 DigiData 1440AD频率 10kHz采样。 系列阻抗经过 60-80%的代偿。 在 -80mV钳制细胞， 每 10 mV为一步长， 电压从 -80mV升到 +50mV刺激 2秒， 记录信号。 化合物 （测试浓度 10μΜ) 对 KCNQ2通道的作用包括整体电导增加 (蘭 和半数 最大激活电压（V1/2)左移。 通过标准的指数方程获得电压激活曲线 （G-V曲线） ， 并计算 V1/2。 CHO cells were transiently transfected into KCNQ 2 channel and current was recorded at room temperature. During the recording, the cells were perfused with an extracellular solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1.5 mM MgCl 2 , 10 mM HEPES and 10 mM Glucose, pH 7.4) in which the compound was dissolved. Electrode (impedance 3-5 megohms) was drawn with a borosilicate glass pipette (Sutter instrument BF150-86-10) and filled with intracellular fluid (145 mM, KCl, lmM MgCl 2 , 5 EGTA, 10 mM HEPES and 5 mM Mg) 2+ -ATP, pH 7.3). Data was acquired with an Axopatch 200B amplifier (Molecular Device), and the signal was filtered at a frequency of 1 kHz and sampled with a software pClamplO interactive interface DigiData 1440AD frequency of 10 kHz. The series impedance is compensated by 60-80%. The cells were clamped at -80 mV, one step per 10 mV, and the voltage was boosted from -80 mV to +50 mV for 2 seconds, and the signal was recorded. The effect of the compound (test concentration 10 μΜ) on the KCNQ 2 channel includes an increase in overall conductance (blue and half maximal activation voltage (V 1/2 ) left shift. A voltage activation curve (GV curve) is obtained by a standard exponential equation, and V 1 is calculated /2 .
(b) 铊流实验方法  (b) Turbulence test method
第一天  first day
第一步： 培养细胞  Step 1: Culturing cells
1.在 75cm2的培养瓶中用完全培养基（ DMEM/F 12 Gibco，添加 500ug/mL G418)培养 KCNQ2 稳定表达细胞株， 密度 80-90%。 1. KCNQ 2 stably expressing cell lines were cultured in a 75 cm 2 flask with complete medium (DMEM/F 12 Gibco, 500 ug/mL G418) at a density of 80-90%.
2. PBS清洗细胞一次  2. Wash the cells once with PBS
3.加入 lmL 0.25%胰酶 (Trypsin-EDTA Gibco, Cat#25200)孵育， 直到细胞变圆， 易脱落。 3. Add lmL 0.25% trypsin (Trypsin-EDTA Gibco, Cat#25200) to incubate until the cells become round and easy to fall off.
4.加入 10ml完全培养基终止胰酶的消化， 用巴斯德管反复吹吸， 使细胞彻底脱落。 4. The digestion of trypsin was stopped by adding 10 ml of complete medium, and the cells were completely detached by repeated pipetting with a Pasteur tube.
5.转移消化液到 50ml的 Falcon管中， 每分钟 1000转离心 5分钟。  5. Transfer the digest to a 50 ml Falcon tube and centrifuge at 1000 rpm for 5 minutes.
6.吸弃培养基， 并用小体积 （0.5mL) 的完全培养基重新悬浮细胞。  6. Aspirate the medium and resuspend the cells in a small volume (0.5 mL) of complete medium.
第二步： 细胞接种  Step 2: Cell seeding
细胞接种到 96孔板中 (Coming, Cat#3894 接种完毕后，轻轻敲打 96孔板边缘使细胞分散， 常温避光 30分钟， 然后 37°C 孵育 16-18小时。  Cells were seeded in 96-well plates (Coming, Cat#3894, after inoculation, gently tap the edge of the 96-well plate to disperse the cells, avoid light for 30 minutes at room temperature, and then incubate at 37 °C for 16-18 hours.
第二天  the next day
1.过夜孵育后， 更换培养基， 加入上样缓冲液 (FluxOR™ detection kit Invitrogen), 室温避 光孵育 90分钟。 2.丢弃上样缓冲液， 加入实验缓冲液。 1. After overnight incubation, change the medium, add the loading buffer (FluxORTM detection kit Invitrogen), and incubate at room temperature for 90 minutes in the dark. 2. Discard the loading buffer and add the experimental buffer.
3.细胞板中加入化合物 （测试浓度 ΙΟμΜ) 。  3. Add the compound to the cell plate (test concentration ΙΟμΜ).
4.细胞和化合物室温避光孵育 20分钟。  4. Incubate cells and compounds for 20 minutes at room temperature in the dark.
5.把细胞板放入检测仪器中 （FDSS Hamamatsu) 。  5. Place the cell plate in the test instrument (FDSS Hamamatsu).
6.每 2秒检测一次荧光信号， 检测 10秒。 第 10秒在细胞板中加入刺激缓冲液。  6. Detect the fluorescence signal every 2 seconds for 10 seconds. A stimulation buffer was added to the cell plate at 10 seconds.
每秒检测荧光信号， 检测 180秒。  The fluorescent signal was detected every second for 180 seconds.
7.检测仪器监测数据质量。  7. Test instrument monitoring data quality.
(c) 原子吸收 Rb+流出高通量测定 (c) Atomic Absorption Rb + Outflow High Throughput Determination
将处于对数生长期的稳转 KCNQ2/Q3通道的 CHO细胞以 2>< 104个 /孔的密度接种于 96 孔培养板。 每个浓度设三复孔。 并设相应浓度的溶媒对照孔。 贴壁生长过夜后， 弃培养液， 加入 200μ1含 RbCl的装载缓冲液， 在 37°C、 5%C02条件下培养 3小时。 然后弃去装载缓冲 液， 用洗涤缓冲液洗涤 3遍。 若筛选通道开放剂， 在去极化缓冲液中稀释待测化合物， 并将 200μ1上述溶液加入细胞中， 反应 10分钟。 孵育 10分钟后， 小心吸取 200 μΐ上清到另一块 96孔板中， 用 ICR8000自动高通量原子吸收测定仪测定 780 nm处的 Rb+原子吸收， 计算相 对流出量。 CHO cells stably transfected into the KCNQ2/Q3 channel in the logarithmic growth phase were seeded at a density of 2><10 4 /well in 96-well culture plates. Three holes are provided for each concentration. The corresponding concentration of the solvent control well is set. After adherent growth overnight, the culture solution was discarded, and 200 μl of a loading buffer containing RbCl was added thereto, and culture was carried out for 3 hours at 37 ° C under 5% CO 2 . The loading buffer was then discarded and washed 3 times with wash buffer. If the channel opener is screened, the test compound is diluted in depolarization buffer, and 200 μl of the above solution is added to the cells for 10 minutes. After incubation for 10 minutes, 200 μL of the supernatant was carefully pipetted into another 96-well plate, and the Rb + atomic absorption at 780 nm was measured by an ICR8000 automatic high-throughput atomic absorption spectrometer to calculate the relative outflow.
Figure imgf000172_0001
29 A A A A C B B
Figure imgf000172_0001
29 AAAACBB
34 B B B B NT NT NT 34 B B B B NT NT NT
38 B B B B C B A  38 B B B B C B A
39 B C B B NT NT NT  39 B C B B NT NT NT
41 B B B B C A A  41 B B B B C A A
46 B B B B NT NT NT  46 B B B B NT NT NT
47 A B B B NT NT B  47 A B B B NT NT B
50 B B B B C B A  50 B B B B C B A
65 A A A A C B A  65 A A A A C B A
73 A A A A B C B  73 A A A A B C B
81 B B B B A B C  81 B B B B A B C
82 A B A A NT NT NT  82 A B A A NT NT NT
83 A A A A C B B  83 A A A A C B B
90 A A A A NT NT B  90 A A A A NT NT B
91 A A A A NT NT NT  91 A A A A NT NT NT
92 A A A A NT NT NT  92 A A A A NT NT NT
94 A B B B NT NT NT  94 A B B B NT NT NT
106 NT NT NT NT B B B  106 NT NT NT NT B B B
107 NT NT NT NT B B A  107 NT NT NT NT B B A
108 NT NT NT NT B B A  108 NT NT NT NT B B A
109 NT NT NT NT B B A  109 NT NT NT NT B B A
114 NT NT NT NT C B A  114 NT NT NT NT C B A
163 NT NT NT NT C B A  163 NT NT NT NT C B A
221 NT NT NT NT B B B  221 NT NT NT NT B B B
222 NT NT NT NT B B B  222 NT NT NT NT B B B
224 NT NT NT NT B A A  224 NT NT NT NT B A A
225 NT NT NT NT B A A  225 NT NT NT NT B A A
227 NT NT NT NT C B A  227 NT NT NT NT C B A
RTG: 瑞替加滨， 2011年 6月被美国 FDA批准上市治疗成人癫痫部分性发作， 为首个 批准上市的 KCNQ开放剂。  RTG: Retigabine, approved by the US FDA in June 2011 for the treatment of partial seizures in adult epilepsy, is the first approved KCNQ opener.
在细胞铊流测试中， 平均激活百分数越大， 表示相应化合物的活性越高， 其中， A≥100， 50≤B<100， 10≤C<50， D<10。  In the cell turbulence test, the greater the percentage of average activation, the higher the activity of the corresponding compound, wherein A ≥ 100, 50 ≤ B < 100, 10 ≤ C < 50, D < 10.
在电生理测试中 I/IO 越大， 表示相应化合物的活性越高， 其中， A≥5， 2<B<5, C<2; - ^Vl/2 (mV) 越大， 表示相应化合物的活性越高， 其中， A≥50， 20≤B<50， C<20。  The greater the I/IO in the electrophysiological test, the higher the activity of the corresponding compound, where A≥5, 2<B<5, C<2; - ^Vl/2 (mV) is larger, indicating the corresponding compound The higher the activity, wherein A ≥ 50, 20 ≤ B < 50, C < 20.
在 Rb+流出测试中， EC5Q越小，表示相应化合物的活性越高，其中 A≤0.1， 0.KB<1 , C>1。In the Rb + efflux test, the smaller the EC 5Q , the higher the activity of the corresponding compound, where A ≤ 0.1, 0. KB < 1, C > 1.
NT表示未测试。 NT means not tested.

Claims

权利要求书  Claim
1、 具有以下通式 （ I ) 的化合 盐:
Figure imgf000174_0001
1. A compound salt of the following formula (I):
Figure imgf000174_0001
(I)  (I)
rz r z
Α选自
Figure imgf000174_0002
或 C3-C1Q杂芳基， 且 A环被 R1和 R2取代; 其中， 当 A为 C3-C1Q杂芳基时， A不为吡咯基和苯并咪唑基； Α selected
Figure imgf000174_0002
Or a C 3 -C 1Q heteroaryl group, and the A ring is substituted by R 1 and R 2 ; wherein, when A is a C 3 -C 1Q heteroaryl group, A is not a pyrrolyl group and a benzimidazolyl group;
R1和 R2各自独立地选自氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6 块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基独立可选地被一个或多个选自氢、 卤 素、 氰基、 硝基、 氨基、 羟基、 CrC6烷基、 CrC6卤代烷基、 CrC6烷氧基、 CrC6卤代烷 氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳 基或 c4-c8杂环烷基的取代基所取代； R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 1Q aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C Substituted with a 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a c 4 -c 8 heterocycloalkyl group;
或者， R1和 R2除以上给定含义之外， 当 R1与 R2连接在相邻的碳原子上时， R1和 R2 与它们所结合的碳原子共同形成五元或六元饱和碳环； 当 R1和 R2连接在同一个碳原子上 时， R1和 R2与它们所结合的碳原子共同形成羰基、 C3-C6环烷基或者苯并 C3-C6环烷基；Alternatively, R 1 and R 2 in addition to the above given meanings, when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 together with the carbon atom to which they are bonded form a five or six member a saturated carbocyclic ring; when R 1 and R 2 are bonded to the same carbon atom, R 1 and R 2 together with the carbon atom to which they are bonded form a carbonyl group, a C 3 -C 6 cycloalkyl group or a benzo C 3 -C 6 cycloalkyl;
R3选自 CrC6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C1Q芳基、 C3-C10杂 芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或 C2-C6块基， 并且被一个或多个选 自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 CrC6烷基、 C3-C6环烷基、 C6-C1Q芳基、 -C6卤代烷基、 -C6烷氧基、 -C6氨基烷基或 -C6卤代烷氧基的取代基所取代；R 3 is selected from the group consisting of C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 10 heteroaryl, C 4 -C 8 heterocycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl or C 2 -C 6 block, and one or more selected from hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, -C 6 haloalkyl, -C 6 alkoxy, -C 6 Substituted by a substituent of an aminoalkyl group or a -C 6 haloalkoxy group;
R4和 R5各自独立地为氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 CrC6氨基烷基、 -C6烷氨基、 -C6卤代烷基或 -C6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C r C 6 aminoalkyl, -C 6 alkylamino, -C 6 haloalkyl Or -C 6 haloalkoxy;
Z2' Z 2 '
X和 Y各自独立地为 CH或 N， 其中， 当 A为 vz3 时， X和 Y为 CH; X and Y are each independently CH or N, wherein, when A is v z3 , X and Y are CH;
Z1选自共价键或 CrC6亚烷基，其中所述 CrC6亚烷基可被一个或多个选自氢或 CrC, 烷基的取代基取代； Z2和 Z5各自独立地为 CH或者 N; Z 1 is selected from a covalent bond or C r C 6 alkylene, wherein said C r C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or C r C, alkyl substituents; Z 2 and Z 5 are each independently CH or N;
Z3和 Z4各自独立地为 C、 CH、 CH2、 N、 NH或者共价键， 其中， Z2和 Z3不同时含 有 N; Z 3 and Z 4 are each independently C, CH, CH 2 , N, NH or a covalent bond, wherein Z 2 and Z 3 do not simultaneously contain N ;
Z6、 Z7和 Z8各自独立地选自 CH2、 （CH2)2、 NH、 NCH3、 NCH2CH3或共价键， 其中 Z5和 Z6、 Z5和 Z7、 Z7和 Z8、 Z8和 Z9不同时含有 N， Z6、 Z7和 Z8不同时为共价键； Z 6 , Z 7 and Z 8 are each independently selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond, wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N, Z 6 , Z 7 and Z 8 are not simultaneously covalent bonds;
Z N、 C或 CH;  Z N, C or CH;
p为 1或 2;  p is 1 or 2;
n为 0-6的整数；  n is an integer from 0 to 6;
B选自 C3-C6环烯基、 C3-C6环烷基、 C6-C1Q芳基、 C2-C1Q杂芳基、 C4-C8杂环烷基或 -C1Q桥环基; B is selected from C 3 -C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C 2 -C 1Q heteroaryl, C 4 -C 8 heterocycloalkyl or -C 1Q bridge ring base;
Figure imgf000175_0001
Figure imgf000175_0001
2、根据权利要求 1所述的化合物或其药学上可接受的盐， 所述化合物具有式（II)结 构， 其中：
Figure imgf000175_0002
p为 1或 2; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has a structure of the formula (II), wherein:
Figure imgf000175_0002
p is 1 or 2;
n为 0或 1 ;  n is 0 or 1;
X和 Y各自独立地为 CH或 N;  X and Y are each independently CH or N;
Z1选自共价键或 -C6亚烷基，其中所述 -C6亚烷基可被一个或多个选自氢或 -Ce 烷基的取代基取代； Z 1 is selected from a covalent bond or a -C 6 alkylene group, wherein the -C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or -C e alkyl;
R3选自 d-C6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C1()芳基、 C3-C10杂 芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或¾- >块基， 并且被一个或多个选 自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 d-C6烷基、 C3-C6环烷基、 C6-C1Q芳基、 CrC6卤代烷基、 ^-^^烷氧基、 CrC6氨基烷基或 ^-^卤代烷氧基的取代基所取代；R 3 is selected from the group consisting of dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1 () aryl, C 3 -C 10 heteroaryl, a C 4 -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a 3⁄4-> block group, and one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Base, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C r C 6 haloalkyl, ^-^ alkoxy, C r C 6 amino Substituted by a substituent of an alkyl or ^-^haloalkoxy group;
R4和 R5各自独立地为氢、 卤素、 氰基、 -C6烷基、 -C6烷氧基、 -C6氨基烷基、 CrC6烷氨基、 CrC6卤代烷基或 CrC6卤代烷氧基； R6和 R7各自独立地选自氢、 卤素、 d-C6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6 环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中 所述 d-C6烷基、 -C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基独立可选地被一个或多个选自氢、 卤素、 氰 基、 硝基、 氨基、 羟基、 d-C6烷基、 -C6卤代烷基、 -C6烷氧基、 -C6卤代烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8 杂环烷基的取代基所取代。 R 4 and R 5 are each independently hydrogen, halogen, cyano, -C 6 alkyl, -C 6 alkoxy, -C 6 aminoalkyl, C r C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy; R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, dC 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 Alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said dC 6 alkyl, -C 6 Alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 - The C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl group is independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, dC 6 alkyl, -C 6 haloalkyl -C 6 alkoxy, -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, Substituted by a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group.
3、 根据权利要求 2所述的化合物或其药学上可接受的盐， 其中：  3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R3选自 d-C6烷基、 C3-C6环烷基或 C6-C1Q芳基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代； R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1Q aryl, and is substituted by one or more substituents selected from hydrogen, halogen, cyano, nitro, amino or hydroxy Replace
R4和 R5各自独立地为 d-C6烷基； R 4 and R 5 are each independently dC 6 alkyl;
R6和 R7各自独立地选自氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 C2-C6链烯基、 C2-C6块基， 其中所述 -C6烷基、 -C6烷氧基、 C2-C6链烯基、 C2-C6块基独立可选地被 一个或多个选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代。 R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 block, wherein The -C 6 alkyl, -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 blocks are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Substituent substitution of a group, an amino group or a hydroxyl group.
4、 根据权利要求 3所述的化合物或其药学上可接受的盐， 其中：  4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein:
Z1为 CH: Z 1 is CH :
R3为甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环 己基、 环戊基、 环丁基或苯基； R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl or phenyl ;
R4和 R5各自独立地为甲基或乙基； R 4 and R 5 are each independently methyl or ethyl;
R6和 R7各自独立地为氢、 氟、 氯、 溴、 甲基、 甲氧基、 三氟甲基或三氟甲氧基。 5、 根据权利要求 1所述的化合物或其药学上可接受的盐， 所述化合物具有式 （III) 结构， 其中：
Figure imgf000176_0001
R 6 and R 7 are each independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl or trifluoromethoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has a structure of the formula (III), wherein:
Figure imgf000176_0001
Z1选自共价键或 -C6亚烷基，其中所述 -C6亚烷基可被一个或多个选自氢或 -C, 烷基的取代基取代； Z 1 is selected from a covalent bond or a -C 6 alkylene group, wherein the -C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or -C, alkyl;
Z2为 CH或者 N; Z 2 is CH or N;
Z3和 Z4各自独立地为 C、 CH、 CH2、 N、 NH或者共价键， 其中， Z2和 Z3不同时含 n为 0或 1 ; Z 3 and Z 4 are each independently C, CH, CH 2 , N, NH or a covalent bond, wherein Z 2 and Z 3 are different n is 0 or 1;
R3选自 CrC6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C1Q芳基、 C3-C10杂 芳基、 c4-c8杂环烷基、 c3-c6环烯基、 c2-c6链烯基或 c2-c6块基， 并且被一个或多个选 自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 CrC6烷基、 C3-C6环烷基、 C6-C1Q芳基、 -C6卤代烷基、 -C6烷氧基、 -C6氨基烷基或 -C6卤代烷氧基的取代基所取代；R 3 is selected from the group consisting of C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 10 heteroaryl, a c 4 -c 8 heterocycloalkyl, c 3 -c 6 cycloalkenyl, c 2 -c 6 alkenyl or c 2 -c 6 block, and one or more selected from the group consisting of hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, -C 6 haloalkyl, -C 6 alkoxy, -C 6 Substituted by a substituent of an aminoalkyl group or a -C 6 haloalkoxy group;
R4和 R5各自独立地为氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 CrC6氨基烷基、 -C6烷氨基、 -C6卤代烷基或 -C6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C r C 6 aminoalkyl, -C 6 alkylamino, -C 6 haloalkyl Or -C 6 haloalkoxy;
R8和 R9各自独立地选自氢、 氰基、 卤素、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6 块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 c4-c8杂环烷基独立可选地被一个或多个选自氢、 卤 素、 氰基、 硝基、 氨基、 羟基、 CrC6烷基、 CrC6卤代烷基、 CrC6烷氧基、 CrC6卤代烷 氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳 基或 c4-c8杂环烷基的取代基所取代； R 8 and R 9 are each independently selected from the group consisting of hydrogen, cyano, halogen, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 - C 1Q aryl, C 3 -C 1Q heteroaryl or c 4 -c 8 heterocycloalkyl are independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C Substituted with a 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a c 4 -c 8 heterocycloalkyl group;
或者除以上给定含义之外， 当 R8和 R9连接在同一个碳原子上时， R8和 R9与它们所 结合的碳原子共同形成羰基、 c3-c6环烷基或者苯并 c3-c6环烷基。 Or in addition to the above given meanings, when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a c 3 -c 6 cycloalkyl group or a benzene group. And c 3 -c 6 cycloalkyl.
6、 根据权利要求 5所述的化合物或其药学上可接受的盐， 其中：  6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein:
Z2、 Z3和 Z4至少有一个基团中含有 N; Z 2 , Z 3 and Z 4 have at least one group containing N;
R3选自 d-C6烷基、 C3-C6环烷基或 C6-C1Q芳基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代； R 3 is selected from dC 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1Q aryl, and is substituted by one or more substituents selected from hydrogen, halogen, cyano, nitro, amino or hydroxy Replace
R4和 R5各自独立地为 d-C6烷基； R 4 and R 5 are each independently dC 6 alkyl;
R8和 R9各自独立地选自氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 -C6烷基、 d-C6 烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基独立 可选地被一个或多个选自氢、 卤素、 d-C6烷基、 -C6卤代烷基、 -C6烷氧基、 -C6 卤代烷氧基的取代基取代； R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group, wherein the -C 6 alkyl group, the dC 6 alkoxy group, the C 3 -C 6 cycloalkyl group , C 3 -C 6 cycloalkenyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, optionally independently selected from one or more selected from the group consisting of hydrogen and halogen Substituted with a substituent of dC 6 alkyl, -C 6 haloalkyl, -C 6 alkoxy, -C 6 haloalkoxy;
或者除以上给定含义之外， 当 R8和 R9连接在同一个碳原子上时， R8和 R9与它们所 结合的碳原子共同形成羰基、 C3-C6环烷基或者苯并 C3-C6环烷基。 Or in addition to the above given meanings, when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a C 3 -C 6 cycloalkyl group or a benzene group. And a C 3 -C 6 cycloalkyl group.
7、 根据权利要求 6所述的化合物或其药学上可接受的盐， 其中：  7. A compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein:
Z1为 CH2; R3为甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环 己基、 环戊基、 环丁基或苯基； Z 1 is CH 2; R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl or phenyl ;
R4和 R5各自独立地为甲基或乙基； R 4 and R 5 are each independently methyl or ethyl;
R8和 R9各自独立地为氢、 氟、 氯、 溴、 甲基、 甲氧基、 三氟甲基、 三氟甲氧基、 苯 基、 2-吡啶基、 3-吡啶基、 4-吡啶基、 吡咯烷基、 哌啶基、 N-吗啉基， 其中所述的苯基独 立可选地被一个或多个选自氢、 卤素、 CrC3烷基、 CrC3卤代烷基、 CrC3烷氧基、 CrC3 卤代烷氧基的取代基取代； R 8 and R 9 are each independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyrrolidinyl, piperidinyl, N- morpholinyl, wherein said phenyl is optionally independently substituted with one or more substituents selected from hydrogen, halo, C r C 3 alkyl, C r C 3 haloalkyl Substituted with a substituent of a Cr C 3 alkoxy group, a C r C 3 haloalkoxy group;
或者除以上给定含义之外， 当 R8和 R9连接在同一个碳原子上时， R8和 R9与它们所 结合的碳原子共同形成羰基、 环丙烷基、 环戊烷基、 环己烷基或者苯并环戊烷基； Or in addition to the above given meanings, when R 8 and R 9 are bonded to the same carbon atom, R 8 and R 9 together with the carbon atom to which they are bonded form a carbonyl group, a cyclopropyl group, a cyclopentyl group, a ring Hexyl or benzocyclopentanyl;
含 Z2、 Z3和 Z4的环状基团为哌啶基、 吡咯烷基或哌嗪基。 The cyclic group containing Z 2 , Z 3 and Z 4 is piperidinyl, pyrrolidinyl or piperazinyl.
8、 根据权利要求 1所述的化合物或其药学上可接受的盐， 所述化合物具有式 （IV) 结构， 其中：  The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which has a structure of the formula (IV), wherein:
Figure imgf000178_0001
Figure imgf000178_0001
X和 Y各自独立地为 CH或 N;  X and Y are each independently CH or N;
Z1选自共价键或 -C6亚烷基，其中所述 -C6亚烷基可被一个或多个选自氢或 -Ce 烷基的取代基取代； Z 1 is selected from a covalent bond or a -C 6 alkylene group, wherein the -C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or -C e alkyl;
R3选自 d-C6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C1()芳基、 C3-C10杂 芳基、 C4-C8杂环烷基、 C3-C6环烯基、 C2-C6链烯基或¾- >块基， 并且被一个或多个选 自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 d-C6烷基、 C3-C6环烷基、 C6-C1Q芳基、 CrC6卤代烷基、 ^-^^烷氧基、 CrC6氨基烷基或 ^-^卤代烷氧基的取代基所取代；R 3 is selected from the group consisting of dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1 () aryl, C 3 -C 10 heteroaryl, a C 4 -C 8 heterocycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 2 -C 6 alkenyl group or a 3⁄4-> block group, and one or more selected from the group consisting of hydrogen, halogen, cyano, and nitrate Base, amino, hydroxy, carbonyl, dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C r C 6 haloalkyl, ^-^ alkoxy, C r C 6 amino Substituted by a substituent of an alkyl or ^-^haloalkoxy group;
R4和 R5各自独立地为氢、 卤素、 氰基、 -C6烷基、 -C6烷氧基、 -C6氨基烷基、 CrC6烷氨基、 CrC6卤代烷基或 CrC6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, -C 6 alkyl, -C 6 alkoxy, -C 6 aminoalkyl, C r C 6 alkylamino, C r C 6 haloalkyl or C r C 6 haloalkoxy;
Z5为 N或 CH; Z 5 is N or CH;
Z6、 Z7和 Z8各自独立地选自 CH2、 （CH2)2、 NH、 NCH3、 NCH2CH3或共价键， 其中 Z5和 Z6、 Z5和 Z7、 Z7和 Z8、 Z8和 Z9不同时含有 N， Z6、 Z7和 Z8不同时为共价键； Z 6 , Z 7 and Z 8 are each independently selected from CH 2 , (CH 2 ) 2 , NH, NCH 3 , NCH 2 CH 3 or a covalent bond, wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain N, Z 6 , Z 7 and Z 8 are not simultaneously covalent bonds;
Z N、 C或 CH;  Z N, C or CH;
n为 0或 1 ; B选自 C3-C6环烯基、 C3-C6环烷基、 C6-C1Q芳基、 C2-C1Q杂芳基、 C4-C8杂环烷基或 C6-C1Q桥环基， 或者无 B环基团； n is 0 or 1; B is selected from C 3 -C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, C 2 -C 1Q heteroaryl, C 4 -C 8 heterocycloalkyl or C 6 -C 1Q bridged ring group, or no B ring group;
Figure imgf000179_0001
Figure imgf000179_0001
R1Q和 R11各自独立地选自氢、 氰基、 卤素、 -C6烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 -C6烷基、 -C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6 块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基独立可选地被一个或多个选自氢、 卤 素、 氰基、 硝基、 氨基、 羟基、 d-C6烷基、 -C6卤代烷基、 -C6烷氧基、 -C6卤代烷 氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳 基或 C4-C8杂环烷基的取代基所取代。 R 1Q and R 11 are each independently selected from the group consisting of hydrogen, cyano, halogen, -C 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 - a C 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group, wherein the -C 6 alkyl group, -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, The C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl group is independently optionally selected from one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, dC 6 alkyl, -C 6 haloalkyl, -C 6 alkoxy, -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 Substituents of a block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group are substituted.
9、 根据权利要求 8所述的化合物或其药学上可接受的盐， 其中：  The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein:
Z1选自共价键或 -C3亚烷基，其中所述 -C3亚烷基可被一个或多个选自氢或 -C3 烷基的取代基取代； Z 1 is selected from a covalent bond or a -C 3 alkylene group, wherein the -C 3 alkylene group may be substituted with one or more substituents selected from hydrogen or -C 3 alkyl;
R3选自 d-C6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C1()芳基、 C3-C10杂 芳基、 C4-C8杂环烷基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰 基、 d-C3烷基、 -C3^代烷基、 -C3烷氧基、 -C3氨基烷基或 -C3 ^代烷氧基的取 代基所取代； R 3 is selected from the group consisting of dC 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1 () aryl, C 3 -C 10 heteroaryl, C 4 -C 8 heterocycloalkyl, and one or more selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carbonyl, dC 3 alkyl, -C 3 ^alkyl, -C 3 Substituted by a substituent of an alkoxy group, a -C 3 aminoalkyl group or a -C 3 ^ alkoxy group;
R4和 R5各自独立地为氢、 卤素、 氰基、 -C3烷基、 -C3烷氧基、 -C3氨基烷基、 C C3烷氨基或 CrC6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, -C 3 alkyl, -C 3 alkoxy, -C 3 aminoalkyl, CC 3 alkylamino or C r C 6 haloalkoxy;
R1Q和 R11各自独立地选自氢、氰基、 卤素、 -C6烷基、 -C6烷氧基，其中所述 -C6 烷基、 CrC6烷氧基独立可选地被一个或多个氢或卤素取代； R 1Q and R 11 are each independently selected from the group consisting of hydrogen, cyano, halogen, -C 6 alkyl, -C 6 alkoxy, wherein the -C 6 alkyl, C r C 6 alkoxy are independently and optionally Substituted by one or more hydrogen or halogen;
Z5为 N或 CH; Z 5 is N or CH;
Z6选自 CH2、 （CH2)2、 顧、 NCH3、 NCH2CH3或共价键； Z 6 is selected from CH 2 , (CH 2 ) 2 , Gu, NCH 3 , NCH 2 CH 3 or a covalent bond;
Z7选自 CH2、 （CH2)2、 NH或共价键； 其中 Z6和 Z7不同时为共价键； Z 7 is selected from CH 2 , (CH 2 ) 2 , NH or a covalent bond; wherein Z 6 and Z 7 are not simultaneously a covalent bond;
Z8选自 (CH2)2、 0¾或1^1; Z 8 is selected from (CH 2 ) 2 , 03⁄4 or 1^1 ;
Z N、 C或 CH; 其中 Z5和 Z6、 Z5和 Z7、 Z7和 Z8、 Z8和 Z9中不同时含有 Nc
Figure imgf000180_0001
ZN, C or CH; wherein Z 5 and Z 6 , Z 5 and Z 7 , Z 7 and Z 8 , Z 8 and Z 9 do not simultaneously contain Nc
Figure imgf000180_0001
11、 根据权利要求 9所述的化合物或其药学上可接受的盐， 其中:  The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein:
R3为甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环 己基、 环戊基、 环丁基、 苯基、 金刚烷基、 2-呋喃基、 吡咯烷基、 吡咯烷酮基或卜 ^， 其中环丙基、 环己基、 环戊基、 环丁基、 苯基、 2-呋喃基、 吡咯烷基独立可选的被一个或 多个选自氟、 氯、 溴、 甲基、 甲氧基、 三氟甲基、 三氟甲氧基、 氨基甲基的取代基取代； R4和 R5各自独立地为氢、 氟、 氯、 溴、 甲基、 乙基、 三氟甲基、 甲氧基或三氟甲氧 基； R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, phenyl , adamantyl, 2-furyl, pyrrolidinyl, pyrrolidinyl or bromo, wherein cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, phenyl, 2-furyl, pyrrolidinyl are independently optional Substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, aminomethyl; R 4 and R 5 are each independently hydrogen , fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy or trifluoromethoxy;
R1Q和 R11各自独立地为氢、 氟、 氯、 溴、 甲基、 乙基、 三氟甲基或氰基； 含 Z5、 Z6、 Z Z8和 Z9的环状基团为哌啶基、 N-甲基哌啶基、 N-乙基哌啶基、 环己 基、 四氢吡咯基、 六氢氮杂卓基或哌嗪基。 R 1Q and R 11 are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or cyano; the cyclic group containing Z 5 , Z 6 , ZZ 8 and Z 9 is Pyridyl, N-methylpiperidinyl, N-ethylpiperidinyl, cyclohexyl, tetrahydropyrrolyl, hexahydroazepine or piperazinyl.
12、 根据权利要求 8所述的化合物或其药学上可接受的盐， 其中：  The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein:
X和 Y为 CH， Z1为亚甲 3为叔丁基， R4和 R5为甲基， Z5为 N， Z6、 Z7和 Z8 为 CH2， Z9为 C， n为 0， B为
Figure imgf000180_0002
R1Q为 H， R11为氟、 氯、 溴或甲基。 X and Y are CH, Z 1 is methylene 3 as tert-butyl, R 4 and R 5 are methyl, Z 5 is N, Z 6 , Z 7 and Z 8 are CH 2 , Z 9 is C, n is 0, B is
Figure imgf000180_0002
R 1Q is H, and R 11 is fluorine, chlorine, bromine or methyl.
13、 根据权利要求 8所述的化合物或其药学上可接受的盐， 其中：  13. A compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein:
X和 Y为 CH， Z1为亚甲基， R3为 R4和 R5为甲基， Z5为 N， Z6为共价键， X and Y are CH, Z 1 is a methylene group, R 3 is R 4 and R 5 is a methyl group, Z 5 is N, and Z 6 is a covalent bond.
Z7和 Z8为 (CH2)2， Z9为 C， n为 0， B为
Figure imgf000180_0003
Ri°为 H， R11为氟、 氯、 溴或甲基。 Z 7 and Z 8 are (CH 2 ) 2 , Z 9 is C, n is 0, and B is
Figure imgf000180_0003
R i° is H and R 11 is fluorine, chlorine, bromine or methyl.
14、 根据权利要求 1所述的化合物或其药学上可接受的盐， 所述化合物具有式 （V) 结构， 其中：
Figure imgf000180_0004
X和 Y各自独立地为 CH或 Ν; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has a structure of the formula (V), wherein:
Figure imgf000180_0004
X and Y are each independently CH or hydrazine;
Ζ1选自共价键或 CrC6亚烷基，其中所述 CrC6亚烷基可被一个或多个选自氢或 CrC6 烷基的取代基取代； Ζ 1 selected from a covalent bond or C r C 6 alkylene, wherein said C r C 6 alkylene group may be substituted with one or more substituents selected from hydrogen or C r C 6 alkyl substituents;
R3选自 CrC6烷基、 C3-C6环烷基、 C6-C8桥环基、 金刚烷基、 C6-C1Q芳基、 C3-C10杂 芳基、 c4-c8杂环烷基、 c3-c6环烯基、 c2-c6链烯基或 c2-c6块基， 并且被一个或多个选 自氢、 卤素、 氰基、 硝基、 氨基、 羟基、 羰基、 CrC6烷基、 C3-C6环烷基、 C6-C1Q芳基、 -C6卤代烷基、 -C6烷氧基、 -C6氨基烷基或 -C6卤代烷氧基的取代基所取代；R 3 is selected from the group consisting of C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 bridged ring, adamantyl, C 6 -C 1Q aryl, C 3 -C 10 heteroaryl, a c 4 -c 8 heterocycloalkyl, c 3 -c 6 cycloalkenyl, c 2 -c 6 alkenyl or c 2 -c 6 block, and one or more selected from the group consisting of hydrogen, halogen, cyano , nitro, amino, hydroxy, carbonyl, C r C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 1Q aryl, -C 6 haloalkyl, -C 6 alkoxy, -C 6 Substituted by a substituent of an aminoalkyl group or a -C 6 haloalkoxy group;
R4和 R5各自独立地为氢、 卤素、 氰基、 CrC6烷基、 CrC6烷氧基、 CrC6氨基烷基、 -C6烷氨基、 -C6卤代烷基或 -C6卤代烷氧基； R 4 and R 5 are each independently hydrogen, halogen, cyano, C r C 6 alkyl, C r C 6 alkoxy, C r C 6 aminoalkyl, -C 6 alkylamino, -C 6 haloalkyl Or -C 6 haloalkoxy;
0为 1()杂芳基， 其中， D不为吡咯基和苯并咪唑基； 0 is a 1() heteroaryl group, wherein D is not a pyrrolyl group and a benzimidazolyl group;
R12和 R13各自独立地选自氢、 卤素、 氰基、 -C6烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 -C6烷基、 -C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6 块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基独立可选地被一个或多个选自卤素、 氰基、硝基、 氨基、羟基、 d-C6烷基、 -C6卤代烷基、 -C6烷氧基、 -C6卤代烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C2-C6链烯基、 C2-C6块基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8 杂环烷基的取代基所取代； R 12 and R 13 are each independently selected from the group consisting of hydrogen, halogen, cyano, -C 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 - a C 6 alkenyl group, a C 2 -C 6 block group, a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group, wherein the -C 6 alkyl group, -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 6 -C 1Q aryl, The C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl group is independently optionally selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, dC 6 alkyl, -C 6 haloalkane , -C 6 alkoxy, -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 block Substituted with a C 6 -C 1Q aryl group, a C 3 -C 1Q heteroaryl group or a C 4 -C 8 heterocycloalkyl group;
或者相邻的 R12和 R13与 D基团上的环原子共同形成三至六元饱和碳环。 Alternatively, adjacent R 12 and R 13 together with a ring atom on the D group form a three to six membered saturated carbocyclic ring.
15、 根据权利要求 12所述的化合物或其药学上可接受的盐， 其中：  The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein:
R3选自 CrC6烷基、 C3-C6环烷基或 C6-C1Q芳基， 并且被一个或多个选自氢、 卤素、 氰基、 硝基、 氨基或羟基的取代基取代； R 3 is selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl or C 6 -C 1Q aryl, and substituted with one or more substituents selected from hydrogen, halo, cyano, nitro, amino or hydroxy Substituent substitution;
R4和 R5各自独立地为 CrC6烷基； R 4 and R 5 are each independently C r C 6 alkyl;
R12和 R13各自独立地选自氢、 卤素、 氰基、 -C6烷基、 d-C6烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基， 其中所述 CrC6烷基、 CrC6 烷氧基、 C3-C6环烷基、 C3-C6环烯基、 C6-C1Q芳基、 C3-C1Q杂芳基或 C4-C8杂环烷基独立 可选地被一个或多个选自氢、 卤素、 氰基、 CrC6烷基、 CrC6卤代烷基、 CrC6烷氧基、 d-C6 ^代烷氧基的取代基取代； R 12 and R 13 are each independently selected from the group consisting of hydrogen, halogen, cyano, -C 6 alkyl, dC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 - C 1Q aryl, C 3 -C 1Q aryl, heteroaryl or C 4 -C 8 heterocycloalkyl, wherein said C r C 6 alkyl, C r C 6 alkoxy, C 3 -C 6 cycloalkyl , C 3 -C 6 cycloalkenyl, C 6 -C 1Q aryl, C 3 -C 1Q heteroaryl or C 4 -C 8 heterocycloalkyl, optionally independently selected from one or more selected from the group consisting of hydrogen and halogen Substituted with a substituent of cyano, C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, dC 6 ^ alkoxy;
或者相邻的 R12和 R13与 D基团上的环原子共同形成五元或六元饱和碳环。 Alternatively, adjacent R 12 and R 13 together with a ring atom on the D group form a five- or six-membered saturated carbocyclic ring.
16、 根据权利要求 13所述的化合物或其药学上可接受的盐， 其中：  The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein:
X和 Y各自独立地为 CH; Z1为 CH2; X and Y are each independently CH; Z 1 is CH 2;
R3为甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁基、 环丙基、 环 己基、 环戊基、 环丁基或苯基； R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl or phenyl ;
R4和 R5各自独立地为甲基或乙基； R 4 and R 5 are each independently methyl or ethyl;
R12和 R13各自独立地为氢、 氰基、 氟、 氯、 溴、 甲基或三氟甲基， 或者相邻的 R12 和 R13与 D基团上的环原子共同形成五元或六元饱和碳环。 R 12 and R 13 are each independently hydrogen, cyano, fluoro, chloro, bromo, methyl or trifluoromethyl, or adjacent R 12 and R 13 together with a ring atom on the D group form a five-membered or Six-membered saturated carbon ring.
17、 12所述的化合物或其药学上可接受的盐， D选自
Figure imgf000182_0001
The compound of 17, 12 or a pharmaceutically acceptable salt thereof, D is selected from
Figure imgf000182_0001
Figure imgf000182_0002
Figure imgf000182_0002
Figure imgf000182_0003
Figure imgf000182_0003
Figure imgf000183_0001
Figure imgf000183_0001
L196L0/£10Z 13/I3d S9I8請 ΪΟΖ OAV L196L0/£10Z 13/I3d S9I8 Please ΪΟΖ OAV
Figure imgf000184_0001
Figure imgf000184_0001
L196L0/£10Z 13/I3d S9I8請 ΪΟΖ OAV
Figure imgf000185_0001
L196L0/£10Z 13/I3d S9I8 Please ΪΟΖ OAV
Figure imgf000185_0001
Figure imgf000186_0001
.T96.0/£lOZN3/X3d 請 ΙΟΖ OAV S8T
Figure imgf000186_0001
.T96.0/£lOZN3/X3d Please ΙΟΖ OAV S8T
Figure imgf000187_0001
Figure imgf000187_0001
Ll96L0/£l0ZSD/lDd S9T81-0/1-T0Z OAV 981 Ll96L0/£l0ZSD/lDd S9T81-0/1-T0Z OAV 981
Figure imgf000188_0001
Figure imgf000188_0001
L196L0/£10Z 13/I3d S9I8請 ΪΟΖ OAV L196L0/£10Z 13/I3d S9I8 Please ΪΟΖ OAV
Figure imgf000189_0001
Figure imgf000189_0001
L196L0/£10Z 13/I3d S9I8請 ΪΟΖ OAV 19、 一种药物组合物， 其含有治疗有效量的如权利要求 1-16中任何一项所述的化合 物或其药学上可接受的盐， 和药学上可接受的载体或稀释剂。 L196L0/£10Z 13/I3d S9I8 Please ΪΟΖ OAV 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
20、 权利要求 1-16中任一项所述的化合物或其药学上可接受的盐在制备增加哺乳动 物特别是人的钾通道中离子流量药物方面的用途。  20. Use of a compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing the ion flux in a potassium channel of a mammal, particularly a human.
21、 权利要求 1-16中任一项所述的化合物或其药学上可接受的盐在制备治疗对钾通 道离子流增加敏感的疾病药物、 特别是在制备治疗中枢神经***疾病药物方面的应用。  The use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease which is sensitive to potassium channel ion flux, particularly for the preparation of a medicament for treating central nervous system diseases .
22、 根据权利要求 19所述的用途， 其中所述疾病选自癫痫、 炎症性疼痛、 神经性疼 痛、 偏头痛、 神经变性疾病、 焦虑障碍、 脑卒中、 ***滥用、 尼古丁戒断、 酒精戒断或 耳鸣。  22. The use according to claim 19, wherein the disease is selected from the group consisting of epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, stroke, ***e abuse, nicotine withdrawal, alcohol withdrawal Or tinnitus.
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